How is the relationship between Juliet and her parents presented in the play Romeo and Juliet Essays

How is the connection among Juliet and her folks introduced in the play Romeo and Juliet Essays How is the connection among Juliet and her folks introduced in the play Romeo and Juliet Paper How is the connection among Juliet and her folks introduced in the play Romeo and Juliet Paper Minister Lawrence scolds Romeo for his whimsicalness in affection. Be that as it may, the Friar consents to wed them with the expectation that the antiquated quarrel of the Montague’s and Capulet’s will end. Later in Act 2 Scene 6 Romeo and Juliet get marry by the Friar, this is perilous provided that Juliet’s family discovers they presumably would repudiate her, so this shows the amount Romeo and Juliet ‘love’ one another, yet it additionally shows how horrifying Juliet’s relationship is with her family on the off chance that they are eager to forsake her. While the medical attendant is telling Juliet of Romeo’s demand, Tybalt sends a test for Romeo to the House of Montague. In Act 3 Scene 1 Benvolio and Mercutio are in an open spot, Benvolio is uncertain that the Capulet’s will show up and a battle will follow. Tybalt states that he is looking for Romeo in any case, Romeo won't acknowledge his demand as he has just barely hitched his cousin, Juliet. At long last it is Tybalt and Mercutio that battle, Mercutio gets wounded under Romero’s arm, clearly Romeo reprimands himself for Mercutio’s wounds. Romeo at that point noxiously pursues Tybalt, when the sorted out battle really happens it is Tybalt that falls, due to this Romeo escapes. The severe brutality that happens in Act 3 Scene 1, just as the desire for the battle, goes about as update that, for all Shakespeare’s accentuation on affection and sentiment, the play ‘Romeo Juliet’ still happens in a world controlled by men, with their convictions of regard and status that will undoubtedly detonate in a contention. This scene is the defining moment of the play. Later on in Act 3 Scene 1 Lady Capulet requests that Romeo must bite the dust, her interest for Montague blood uncovers the degree of contempt between the two families. In any case, in light of the fact that Tybalt had killed Mercutio, Romeo’s sentence was just that of outcast, as opposed to death. This scene causes the peruser to feel compassion towards Romeo and Juliet as they just barely got hitched, they didn’t even get an opportunity to praise this marriage before Romeo was expelled from Verona. When Juliet learns of this news she doesn’t recognize what feeling she should feel, at the same time, at long last chooses to remain faithful to her significant other. Act 3 Scene 5 is the most urgent scene in the adjustment in connection among Juliet and her folks. This scene is brimming with pressure emotional incongruity and ambiguousness. Juliet has recently spent her first and the previous evening with Romeo, the medical attendant cautions them that her mom is drawing nearer. When Juliet’s mother enters she misreads Juliet’s feelings, she trusts her misery is from grieving her cousin, Tybalt. Her distress is really a direct result of Romeo’s banish. Woman Capulet approaches â€Å"Evermore Weeping for you cousin’s passing? What, shrink thou wash him from his grave with tears† These are for the most part facetious inquiries, Lady Capulet wishes Juliet to quit crying as an excess of misery isn't shrewd. Woman Capulet appears to be pitiless in what she says here, however she could be attempting to animate Juliet. Notwithstanding, she adds that to show so much misery shows â€Å"some need of wit† this suggests Juliet is inept which shows how unfeeling Lady Capulet is towards her little girl. At that point she likewise makes an inaccurate supposition â€Å"Well, young lady, thou weep’st less for his demise/As that the lowlife lives which butchered him†. Woman Capulet is more angry than distressed, she just wishes for retribution on the Montague that slaughtered a valuable Capulet, she expect Juliet feels a similar way. Clearly Juliet doesn’t feel thusly, she says to herself â€Å"Villain and he be numerous miles to shreds â€Å", she continues to state to her mom â€Å"God excuse him, I do with everything that is in me: And yet no man like he doth lament my heart† these are the main uncertain lines in this demonstration, it is questionable in light of the fact that it has two implications. To herself she is stating that Romeo would never be a lowlife, to Lady Capulet she is stating â€Å"God pardon him† just as God is the one in particular who could concede Romeo absolution. These lines strengthen the amount Juliet cherishes Romeo; this has the impact of working up the pressure all through the scene. Yet, she vigorously recommends to her mom that Romeo laments her heart since he isn't with her, however Lady Capulet misconstrues this â€Å"That is on the grounds that the double crosser killer lives†. Woman Capulet proceeds to communicate her contempt for Romeo, uncovering how she wishes to harm him so he can lie close to Tybalt, she at that point says she trusts this idea fulfills Juliet. Juliet answers, â€Å"Indeed I never will be fulfilled/With Romeo, till I view him †dead/Is my poor heart, so for a brother vexed. † This is likewise uncertain, Juliet is deluding her mom. Woman Capulet believes that Juliet will never be fulfilled until Romeo is dead, in any case, what Juliet truly implies is that her heart is dead and she will never be fulfilled until her better half is with her again. Woman Capulet continues to disclose to her little girl of â€Å"joyful tidings†, she educates Juliet that Lord Capulet has masterminded her to wed Paris next Thursday, this elevates the sensational strain as they crowd definitely know Juliet is hitched. Juliet, horrified, will not do as such, â€Å"He will not make me there a cheerful lady of the hour. Woman Capulet answers â€Å"Here comes your dad, let him know so yourself; And perceive how he will take it at your hands† These lines are exceptionally pernicious as Juliet has seen Capulet’s response and contention with Tybalt, and Lady Capulet is helping Juliet to remember that. When Capulet enters he additionally misjudges Juliet’s pity, yet he shows up increasingly thoughtful; he makes an all-encompassing representation, only one of the strategies Shakespeare utilizes, by contrasting Juliet with a pontoon, the ocean and wind â€Å"Thou fakes a bark, an ocean, a wind†. Juliet’s body is the pontoon, her eyes are the ocean and her murmurs are the breeze. He at that point inquires as to whether she has educated Juliet regarding their order, she answers harshly â€Å"Ay, sir, however she will none, she gives you much obliged. I would the nitwit were hitched to her grave. † This was an incredibly unforgiving, rude comment, which represents how little Lady Capulet thought about Juliet and how malignant she was towards her. Be that as it may, she may have said it on the grounds that Juliet was ignoring her father’s orders; this was illegal in the 150 hundreds. Spouses additionally needed to comply with their husbands, so she was unable to concur with Juliet as she couldn’t even mull over being unfaithful. Shakespeare creates strain in this scene with the appearance of Lord Capulet and through her organized marriage. Shakespeare utilizes numerous language strategies including unfortunate error and the utilization of similitudes, these improve the strain. Likewise Capulet adjusts from a minding to a maddened dad as his style of language and tone change. He begins by consoling Juliet as she cries. Be that as it may, when he finds Juliet doesn't wish to wed Paris, the language he utilizes totally transforms; he addresses her as an outsider looking in, utilizing â€Å"she† and â€Å"her†. I think he is separating himself from Juliet as she accomplished something reprehensible in his eyes, in his words that tail he detonates in rage. â€Å"Out, you green-ailment remains! out, you things! † He is taking steps to abandon Juliet, this demonstrates a formerly obscure side to Capulet as he affronts Juliet, â€Å"You fat face! † Shakespeare underlines the power of these put-down by the utilization of shout denotes, this has the impact of expanding the pressure when conveyed in a play. Master Capulet likewise utilizes objectives in his threatening tirades, â€Å"thank† â€Å"look†. Likewise Capulet is appeared as immature and insignificant when he impersonates Juliet. I for one think Capulet ought to have asked Juliet for what reason she would not like to wed, instead of attempting to menace her into it by undermining and seething at her. Be that as it may, this wouldn’t have been normal in those occasions as fathers orders was law. Additionally in this scene a great deal of incongruity is made; Juliet has no other choice yet to wed Paris or, in all likelihood she will be destitute. I felt that Lady Capulet would be increasingly thoughtful toward her girl, however in reality it was the medical attendant who came to Juliet’s barrier; â€Å"God in paradise favor her! You are at fault, my master, to rate her so. † But, Lady Capulet additionally needed to obey Capulet’s orders, she wasn’t ready to concur with her little girl or she would be similarly situated, â€Å"I’ll provide for you my companion; And you be not, hang, ask, starve, kick the bucket in the streets†. Capulet needed to show his power as he suspected Juliet was resisting him and being thankless. Before Lady Capulet withdraws Juliet argues for her to defer the marriage, if not she will kill herself, â€Å"Delay this marriage for a month, seven days, or in the event that you don't, make the wedding bed in that diminish landmark where Tybalt lies. Woman Capulet shows not the smallest trace of empathy towards her little girl as she won't help her, â€Å"Talk not to me, for I’ll not express a word. Do as thou wither, for I have finished with thee. † This shows she thinks about Juliet, or she could have believed that Juliet’s danger was unfilled. At the point when her mom leaves Juliet goes to the Nurse with her issues, wanting to discover comfort. This shows Juliet thinks more about the Nurse than her mom, the crowd definitely knows this as Juliet trusted in the Nurse when she was thinking about wedding Romeo not her mom. However, the Nurse concurs with her dad, asking Juliet to wed Paris. I think the Nurse was just attempting to hel

Jack London Free Essays

Week 61 Week 6 Joseph Robbins HUM 335 Christina Baker April 21, 2013 Week 62 1. From â€Å"The Slaughter of Pigeons† in Chapter 6, What is the author’s guarantee about the morals of chasing? What explicit words does the creator use to â€Å"stack the evidence† for his case? Information on the characters and their chronicles isn't important to acknowledge â€Å"The Slaughter of the Pigeons† on the grounds that we can decipher through each character’s activities Cooper’s basic message. The residents terminating erratically into the group is a generally crazy picture. We will compose a custom article test on Jack London or on the other hand any comparable theme just for you Request Now Between the killing of different feathered creatures with one visually impaired shot to the releasing of the overwhelmed turn ordinance on the group, it isn’t difficult to see Cooper’s analysis of the settler’s imprudent pulverization of untamed life. The character of Leather-Stocking fills in as an ecological model. He dexterously shows killing a solitary pigeon and utilizations the endeavor to help permeate the locals with a touch of traditionalist intelligence, not to take from nature more than what they need. Having imparted the story’s moral, Cooper shuts the scene with the picture of the huge number of dead or kicking the bucket fowls tossed over the ground. Likewise read The Story of an Eyewitness Essay Analysis This picture is an away from of the revolting pointlessness of the settler’s butcher. 2. From â€Å"A Blizzard under Blue Sky† in Chapter 6, Write a â€Å"claim of policy† that this story proposes for a person who is doing combating gloom. Does the case have merit? Clarify. I thought â€Å"A Blizzard Under Blue Sky† was a magnificent story and accomplished precisely what it expected to. It incited joy, perhaps shock, in view of the way that after setting out Houston was at first suspicious about the mending intensity of the normal world, and thusly discovered how progressive an extraordinary encounter can be. Is most intriguing that Houston Week 63 promptly turned down enemy of discouragement drug. The vast majority would be excited at the possibility of a pill filling the void in their lives. Pam Houston had an opposite view: â€Å"one of the things I love the most about the characteristic world is the manner in which it gives you what is beneficial for you regardless of whether you don’t know it at that point. † The significant thing to note here is that she didn't have a clue how nature would recuperate her, however she had a steadfast confidence that it would even in incredibly unforgiving conditions. In the event that you accept that nature is your adversary, than it is, however that is valid with all parts of life. The case above benefits itself by tolerating life as what it is and realizing that no one but you can roll out an improvement. 3. From the sonnet â€Å"Saint Francis and the Sow† in Chapter 6, What is Kinnell’s guarantee? On what logical intrigue does the artist depend? Point out and assess explicit instances of this intrigue. Galway Kinnell’s â€Å"Saint Francis and the Sow† focuses on numerous topics that include honesty, blame, excellence, and exquisiteness. Toward the start of the sonnet, Kinnell alludes to â€Å"The bud† as â€Å"all things†. A bud is basically the principal period of a blossoms life. Be that as it may, buds can speak to a wide range of things, including the capability of excellence to come, immaculateness, and blamelessness. A bud is unadulterated and I accept alludes to early stages, which likewise infers that it’s crude. The astute case in the initial two lines of the sonnet propose that the bud has pervasive attributes. The kind of attributes what impact a type of substance on â€Å"all things†. That being stated, it’s very unexpected how something as amazing as â€Å"The bud† sits on a line without anyone else in the sonnet. It’s as though the bud is really helpless. Likewise, included all through the sonnet are faculties and depictions of the pig. â€Å"From the earthen nose completely during that Time 64 grain and slops to the profound twist of the tail†. Kinnell utilizes the sow to separate its soul and body. Certain lines from this sonnet respect a considerable amount of individuals in this day in time of society. â€Å"Though some of the time it is vital, to reteach a thing its loveliness†. The line recommends that it’s regularly important to remind others that there isn’t one standard of physical beauty. Everything is stunning in its own one of a kind way. A huge part of our way of life is focused on a completely off-base impression of what excellence really is. This sonnet impacts people to attempt to adore themselves for what their identity is, not what another person figures you ought to be. â€Å"To put a hand on its forehead, of the blossom, and retell it in words and in contact, it is lovely†. Kinnell couldn't have made a superior showing reaffirming this to the peruser with â€Å"Saint Francis and the Sow†. . From â€Å"Solitude (from Walden, or Life in the Woods) in Chapter 6, Thoreau states â€Å"I think that its healthy to be along most of the time. † Discuss a few reasons the creator gives in contending to the temperance of isolation. How does Nature add to his contention? He isolates himself from his reasoning psyche, say ing that the piece of the self that reflects internal can be made outside to oneself. The errands and occasions of life are outside to us. In particular, this outside piece of oneself has a place with nobody †it is totally autonomous. In this condition, isolation is relative and not forlorn. Society, then again, is modest and meddles with our feeling of ourselves, since we don't have the space to think. We get in each other’s way. We do Week 65 not have to contact individuals to comprehend their worth/significance to us. In the forested areas, God and Mother Earth are his organization, which is bounty for him. In this condition, there are sure things more valuable than everything else. One is the morning air, which won’t keep even until early afternoon. Keep it on the off chance that you can, he says, however it will get stale entirely quick. Article: Mankind's history is covered with model where a couple of individual gambled life and appendages to wander into the obscure, which at that point came to be found, on account of their soul of adventurism or as some would state, fool tough boasting. Obviously, certain names ring a bell, Christopher Columbus, Captain James Cook, Lois and Clark and so forth. There is another side to this story of acclaim too. Indeed, even the examples of overcoming adversity once in a while had a ring of disappointment about itself. An individual may be a pioneer in the field of revelation however the his rewards for so much hard work are delighted in by the individuals who tail him. He may in reality have filled in as n extra instrument in the way to disclosure, in the large plans of things. Much to our dismay about the glaring disappointments of the individuals who set out to and never lived to tell the story of their alleged greatness? The component of nature, the new landscape, the outrageous climate and unforeseeable conditions all piled up as commendable impediments in the method of any individual who set out to investigate its insider facts and breadth, and encouraged and thought of defeating these. Despite the fact that the primary character predicts the enormous difficulties lying in front of him, he embarks to seek after it, during a Time 66 ixture of numbness, lack of concern and resolve. Here and there everybody wants to surrender, and the main thing an individual can depend on is his will to endure. Surrendering is conceding rout, in each situation. Thinking about the excursion itself, which is introduced as a noteworthy snag, it presents a difference. The complexity is between the level of trouble and the absence of handle for the gravity of the circumstance which introduces itself. Maybe, no place is this absence of readiness for the excursion more displayed than where he finds himself in an opening (snapshot of peril) e. g. where he recognizes this. Maybe the most convincing proof of this bonehead hard arrogance that is verging on frenzy is obvious through the accompanying. I went through 15 months in a battle zone with the US Army and on the off chance that it wasn’t for the individuals I was with, I would have surrendered quite a while in the past. I was harmed, intellectually and truly however I realized that there was something such a great amount of better to live for when this was finished. We as a whole battle with surrendering, however we gain such a great amount by not surrendering and I would prefer to be presumptuous than any time in recent memory surrender. Week 67 References James, M. also, Merickel, Alan P. (2011). Understanding writing and composing argument,4th ed. Longman: Boston, MA. Instructions to refer to Jack London, Papers Jack London Free Essays string(67) the nine horrendous circles incorporated with the channel of Dante’s Hell. ANQ: A Quarterly Journal of Short Articles, Notes, and Reviews, Vol. 23, No. 3, 172â€178, 2010 Copyright  © Taylor Francis Group, LLC ISSN: 0895-769X DOI: 10. We will compose a custom article test on Jack London or on the other hand any comparative point just for you Request Now 1080/08957691003712363 R USSELL M. H ILLIER Providence College Crystal Beards and Dantean In? uence in Jack London’s â€Å"To Build a Fire (II)† James I. McClintock has depicted Jack London’s great short story â€Å"To Build a Fire (II)† as the â€Å"most develop articulation of his pessimism† (116). In what follows, I wish to investigate the likelihood that there is a considerable component of profound moral story employable in London’s account. London initially imagined his story as an ethical tale and a preventative account to American youth never to travel alone. To this end, London distributed the story in Youth’s Companion. In its ? nal variant, however, the story expected determinedly darker and increasingly vile tones. In catching the threat of the severe northland, London was drawing upon his own movements in the Klondike, yet I would contend that his account was likewise motivated by a combination of his experience of the brutal and somber environ

How to Add Elements and split under Blogger Sidebar

How to Add Elements and split under Blogger Sidebar Often we see many blogger template contain that split sidebar that helps the blogger to add Blogger labels vertically or we can easily add 160px X 600px Ad unit. So this is very effective for blogger to save space. Because if you don't split sidebar and add any widget then it will occupy the whole space. Adding element (add a gadget) under the existing sidebar is very simple trick. If you are well known about blog coding then understanding the code will be much easier. So I am sharing with you the trick that will help you to split your current blogger sidebar into 2 column. just follow the simple steps from below. Step 1Login to your bloggeraccountand Click onTemplate- Step 2Now click onEdit HTML- Unfold code Step 3Now find like below code by Pressing Ctrl+F #sidebar-wrapper {width: 300px;float: $startSide;word-wrap: break-word; /* fix for long text breaking sidebar float in IE */overflow: hidden; /* fix for long non-text content breaking IE sidebar float */} Note that sidebar-wrapper width may 280px, 300px or 310px or any other number so don't worry. just focus on Sidebar-Wrapper. Step 4And now replace the code by below code. #sidebar-wrapper {width:320px;float:right;font-family:Oswald,Georgia,Verdana,Geneva,Sans-serif,Arial,Helvetica;margin:10px auto;word-wrap:break-word;overflow:hidden;padding:0.5% 0;} Step 5Now add the below code after above code (from Step 4) #Spice-left{width:50%;float:left;font-family:Oswald,Georgia,Verdana,Geneva,Sans-serif,Arial,Helvetica;word-wrap:break-word;overflow:hidden;}#Spice-right{width:50%;float:right;font-family:Oswald,Georgia,Verdana,Geneva,Sans-serif,Arial,Helvetica;word-wrap:break-word;overflow:hidden;} Step 6 Now find the code like below div id='sidebar-wrapper'b:section class='sidebar' id='sidebar' preferred='yes' /b:section Step 7 Finally add the below code after /b:section b:section class='sidebar' id='Spice-left' preferred='yes'/b:section class='sidebar' id='Spice-right' preferred='yes'/ The final code will be look like below- div id='sidebar-wrapper'b:section class='sidebar' id='sidebar' preferred='yes' /b:sectionb:section class='sidebar' id='Spice-left' preferred='yes'/b:section class='sidebar' id='Spice-right' preferred='yes'/ Now check your blog layout view and see that your blog sidebar has split into 2 column. There are some optional step which you may use from below. Optional Step If you wish to fix your new splited elements under sidebar according to your blog widget setting then please add the below code after the code from Step 5. #Spice-left .widget-content{margin:3px 3px 3px 3px;word-wrap:break-word;overflow:hidden;}#Spice-left li,.column li {line-height: 18px;padding: 3px 10px;text-decoration: none; }#Spice-left ul{margin:0;padding:0;list-style:none;}#Spice-right .widget-content{margin:3px 3px 3px 3px;word-wrap:break-word;overflow:hidden;}#Spice-right li,.column li {line-height: 18px;padding: 3px 10px;text-decoration: none; }#Spice-right ul{margin:0;padding:0;list-style:none;}#Spice-left h2{Width:90%;color:#252525;padding:5px 0 5px 10px;;margin bottom:10px;position:relative;border-bottom:2px solid #252525;}#Spice-right h2{Width:90%;color:#252525;padding:5px 0 5px 10px;margin-bottom:10px;position:relative;border-bottom:2px solid #252525;}#sidebar h2{color:#252525;font-family:Oswald,Georgia,Verdana,Geneva,Sans-serif,Arial,Helvetica; padding:6px;margin-bottom:10px;position:relative;border-bottom:2px solid #252525;} If you have any problem then feel free to contact with me. I will reply you as soon as possible.

Analysis Of The Book The Twelfth Day - 1210 Words

As the dust settled and the sky’s cleared we were left with the horrific realization that our nation has been attacked. This would be September 11, 2001, or better known as 9-11. This day, I believe, was one of the most if not most traumatic days in our nation’s history. On this day two American Airplanes were hijacked and crashed into the World Trade Center in New York City, leaving our nation distraught. Prior to reading the book â€Å"The Eleventh Day† I had a general understanding of the September 11, 2001 terrorist attacks, but after reading I soon found out knowledge that shocked, saddened and angered me. This book breaks down the personal accounts of September 11, how the conspirators succeeded and also gives knowledge as to who the†¦show more content†¦These people were the extremist group al-Qaeda. This group though was headed by Osama bin Laden. Osama bin Laden was an extremist who we hold responsible for the terrorist attack. In chapter 15 of the book the author identifies Osama bin Laden as the protagonist,. â€Å"That officialdom gave us, that young men loyal to al-Qaeda and Bin Laden were responsible†. In Part V, the author starts to build the case for Bin Laden as the protagonist. In the words of Michael scheuer, â€Å"a truly dangerous, dangerous man†. We are then led through the development of the organization of Bin Laden s terrorist group and the selection of the individuals who would carry out the plans. Bin Laden was the sole leader in the development ment of the terror plot. The author also speaks about Saudi Arabians. â€Å"In 2001 sympathy for al-Qaeda and Bin Laden was widespread across the Saudi Society†. I find this to be very shocking. This shows that Bin Laden had his ideologies wide spread and instilled in many people across the Middle East and world. When thinking about 9/11 I become very curious on how such a prolific event could take place in our great nation. Now what went wrong? There were many things that went wrong including the fact that there was mass confusion among Air Traffic control operators, but one the main things that went wrong was the acquisition of Visas and US identification by the al-Qaeda terrorist. How were the

All Of Me By Kim Noble - 2109 Words

Sometimes Ignorance is Bliss October 6th 2011 â€Å"All of Me† was release by Kim Noble, a women who suffers from dissociative identity disorder (DID). This disorder was formally known as multiple personality disorder and is when one body has many different personalities or fragments of personalities(Durand,Barlow, 2016,187). This personal narrative tells the gut wrenching story of one women who has over 100 personalities, through 20 different characters and her journey to accept she has DID. This memoir is a narration that goes through Kim’s journey from abuse, to questioning who/what she is, what is wrong with her, also depicted are her struggles with blackouts, and having alter ego’s that have â€Å"sub-disorders.† There is the moving story that is shared of their daughter Aimee being taken away and the effect it had on the alters, the fight they fought to get sole custody back is heartfelt. November 21, 1960 was when Kim Noble entered this world to James and Dorothy Noble and her sister Lorraine at the Mayday hospital in Croydon, south London. Kim lived with her family growing up in Shirley, she later moved into her Grandparents 3 bedroom house when her Grandfather passed away. The family was very close and she was blessed to have many family relatives around the area. At the age of 5 was when Kim remember’s her world becoming â€Å"splintered and fractured,† her now one mind was split up into many. Her body was a host to more than 20 different personalities/alters and her 369 pageShow MoreRelatedAnalysis Of The Poem Patricia Talks858 Words   |  4 Pagesand participate in the Girls Brigade, similar things that normal girls did growing up then and now (Nobles,2006,43-44). She had friends and played with kids in her neighborhood she was sometimes a ‘normal’ girl. 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Why Was China Such an Advanced Society for So Long Essay

Why Was China Such an Advanced Society for So Long? Throughout history, China has been the center of many developments allowing for it to establish itself as an advanced society, one that has lasted through a number of dynastic cycles, an attempt towards the creation of a Republic, and still existing, People’s Republic of China, under the rule of China’s Communist party. Throughout this turbulent history China has made much advancement in site of its setbacks and has allowed itself to grow immensely and increase its stature, making it one of the world’s great powers. While most of China’s history can be analyzed through it its extensive periods under dynastic rule, the best way to look as China in terms of a successful advanced†¦show more content†¦Despite this reverence for Confucian scholarship and increased education during the time period, civil service examinations were briefly discontinued for a short amount of time, Hongwu consolidated po wer, and a strong central police, the Jinyiwei, was created to help consolidate this power. (Hucker, 13; Fairbank, 130). Under this dynasty, merchants and markets were rethought and in revisiting this shift in prevailing attitudes, one can see how China emerged as one of History’s advanced societies. This changing view was made apparent as people realized the inherent worth of merchants in relation to their impact on society as a whole. The acts of commerce merchants undertook, led to increased state revenues, used to fund education of China’s educated bureaucracy (Brook, 90–93, 129–130, 151). This trend of social upheaval was a continued and more pronounced growth of general trends that were also seen in Chinese society under the Song dynasty (Gernet, 60–61, 68–69). As the state realized the potential benefits that could come through market forces they ultimately realized these merchants could help value resources (Brook, 102). In the incre asingly global economy the Ming mainly traded large amounts of finer finished goods, while many of their imports could be viewed as an integral part of their internal function. Silk and porcelain are two products that the Chinese have been historically associated with. ThisShow MoreRelatedGuns, Germs, And Steel Essay1174 Words   |  5 PagesGuns, Germs, and Steel Essay The historical book Gun, Germs, and Steel written by Jared Diamond explains a variety of different themes as to why the world came to be as it is today. The differences in technology and advances differing between other countries. 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Dutch Colonisation free essay sample

Europeans. one of them was the Netherlands, they call themselves the Dutch. The Dutch started ruling in Indonesia from 1603 and ended in 1942 by a japanese invasion in world war 2. Between 1602 1798 indonesians were under the control of the Dutch east india company. The Indonesians suffered exploitation of its labor force, this led to a huge uprising against the Dutch rule which contributed to their demise. The Dutch colonization impacted Indonesia in many ways, which was important to the development of Indonesia. DUTCH RULE IN INDONESIA The Dutch did not treat the Indonesians very well, they did not rule all over Indonesia, because some of the countries in indonesia were independent. The Dutch colonized Indonesia for many purposes, mainly for economical purposes, they were interested in the exotic resources found in Indonesia, as Indonesia was known for having resources such as coffee, sugar, and spices such as nutmeg, cloves, black pepper and cinnamon. We will write a custom essay sample on Dutch Colonisation or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page THE DUTCH EAST INDIA COMPANY SUPPRESSED INDONESIA After a short period of trading spices, during 1602 the VOC (Vereenigde Oost Indische Compagnie) or Netherland’s united east india company was formed. Around 1619 after the slow process of Netherland’s industrialization, the VOC indirectly colonized indonesia. Their initial purpose was to dominate the trade in indonesia and form a monopoly of trade against other European countries, who they were competing against. The VOC slowly got more control over Indonesia as they built headquarters in Batavia, Banda, Tidore, Java, and Makasa. INDONESIA UNDER THE DUTCH RULE Under the dutch rule, Central Java suffered starvation from 1900 to 1902 they only suffered for two years?. The Dutch exploited the colony, its natural resources, and the labor force. The Dutch were interested in gaining high profits from the labor and resources they extracted from Indonesia. The Dutch use to make people grow crops,make spices,etc never use etc because it means you cannot think of anything else to write. When,all the crops and spices were made they use to be sent to their country and,when it would be ready to be sold they use to get it back to Indonesia and sell it to the people of Indonesia. This is how they made profit very fast and easily. The Dutch established closer governmental controls over the colony. In l830 this political control was improved by the Cultuurstelsel (Cultivation System), it is an economic system by which the government took direct control over the development of the agriculture. The natives were required to work sixty-six days for the government. INDONESIA’S RESISTANCE The Java War of 1825-30 was the last resistance of the Javanese to Dutch rule. It was led by Pangeran Diponegoro (ca. 1785-1855), eldest son of the sultan of Yogyakarta. His education was a combination of both Islamic and mystical elements. The cause of this war in 1825 was the Dutch decision to build a road across a piece of his property that contained a sacred tomb. Therefore the Java War started, it was a bitter guerrilla conflict in which as many as 200,000 Javanese died in fighting, the population of Java at the end of the eighteenth century was only 3 million. The territories of Yogyakarta and Surakarta were weakened. This paragraph reads very similar to one from the Mongabay website, you need to be careful not to plagiarize information INDONESIAN INDEPENDENCE Due to bankruptcy, the VOC was dissolved in 1800. During World War II, 1942-1945, the Japanese occupied Indonesia. Although short-lived, the occupation enabled Indonesians to arm themselves for the very first time. Shortly after Japans defeat in WWII, Sukarno and Hatta proclaimed Indonesia an independent state, and they became the founding fathers of the new country. When the Dutch returned and tried to re-establish colonial rule, armed Indonesians resisted. The Dutch were forced to recognize an independent Indonesia in 1949. COLONIZATION IMPACTS ON INDONESIA The Dutch established Java as the center of the East Indies, which explains hy Java is the economic, political and most populous island in Indonesia. Well, the Dutch left both good and bad impacts on indonesia some of the good things were the development of roads, infrastructure, closer interaction between Western and Eastern culture and education. Christian missionaries also converted some of the Bataks, Ambonese and Papuans. Some of the bad things were the exploitation of Ind onesian resources and labour and discrimination against Eurasians and non-white people in jobs in the civil service and military. The Dutch wanted access to Indonesian natural resources to bring back to Europe and trade. They used the Indonesians as slaves to farm many of Indonesian natural resources. The Dutch became rich from these practices while the Indonesians suffered and became angry. The combination of the anger towards the dutch, and the fact that they became more educated from the Dutch, the indonesians started to develop their own opinions and rebelled against the dutch which eventually led to Indonesian independence.

Review of Part 3 of Omnivores Dilemma free essay sample

FoodReview of Part 3 of The Omnivore’s Dilemma ENGL-135 Advanced Composition Professor Edmondson William McGuire In Part 3, Chapters 15, 16, and 17 of The Omnivore’s Dilemma, Michael Pollan explores looking foraging for different foods, the ethics of hunting animals and harvesting the meat from them, and giving a brief look into what brought about the paradox of The Omnivore’s Dilemma. Chapters 15, 16, and 17 bring up a lot of good points about foraging and hunting and Pollan provides through detail and research on the topics, but upon reading these chapters you find it lacking content that will keep you engaged and the material can be pretty dry at times while you get a little bit of disorganization from random topics. Chapter 15 of Omnivores Dilemma was a short chapter on how Pollan is preparing to make a meal from all of the foraging groups. Fruits, vegetables, fungi, and meat were the components that made up this meal, he wanted to find and gather enough from each group to make his first. We will write a custom essay sample on Review of Part 3 of Omnivores Dilemma or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Pollan had just moved to California, so his unfamiliarity with the area was a disadvantage, so he decided to hire a companion to help him on his quest. Chapter 16 takes the reader to a different venue, Pollan discusses the beginnings of The Omnivore’s Dilemma through a research paper that was written in 1976 by Paul Rozin and titled The Selection of Foods by Rats, Humans, and Other Animals. Pollan expresses how similar we are to rats that we are omnivores, but unlike rats, we have lost our instinct of choosing food and follow advertisements as our guide. He then goes on to suggest that the problems stem from capitalistic gains and the pursuit of revenue. In chapter 17 we are taken back to Pollan on his foraging quest he started in chapter 15. This chapter looks more at the ethics of hunting and eating animals that are not processed in processing plants like we are so use to seeing. Pollan brings up reasoning on why he is a meat eater and battles with the struggle on if eating meat at a steakhouse is morally right and ethical. He goes into detail about the way the animal lived and if the animal had a long, happy, humane life. The author concludes that if we look away from how the animal goes from being on the farm to a freezer in the supermarket then people turn vegetarian and if we can’t look away then we have to find a way to accept it and determine if the animal endured a lifetime of suffering. Part 3 in the book meets two out of the three common expectations and displays some strong descriptive wording to give you a sense of imagery when you read certain parts of the book as well as give you a good understanding on the point he is trying to get across. An example of one of the statements that he uses to paint a picture for you and try to bring you there is â€Å"I began to notice things. I noticed the soft yellow globes of chamomile edging the path I hiked most afternoons, and spotted clumps of miner’s lettuce off in the shade (Claytonia, a succulent coin-shaped green I had once grown in my Connecticut garden) and wild mustard out in the sun. (Angelo called it rapini, and said the young leaves were delicious sauteed in olive oil and garlic. ) There were blackberries in flower and the occasional edible bird: a few quail, a pair of doves. (Pollan, pg. 285) Another strength in this book is the subject matter that pertains to what the author is trying to convey to the reader, Pollan is trying to show the readers that the way we use to obtain and eat food is ever changing and will continue to change and we are easy to influence as it pertains to our diets, he does well in keeping to the theme of his book. The weaknesses of Part 3 cover two of the three common expectations and they are the lack of engagement for the reader and the order in which the subject matter is presented. This book is not tailored for someone who loves to read fantasy or action, something that will leave you hanging on the edge of your seat wanting more. Instead what you get is someone detailing his experiences and research that supports a lot of his ideas, ethics of eating animals, and corn sex, alas no explosions or protagonist/antagonist struggle. I found myself dozing off a few times feeling like I was in an agriculture lecture or biology class. The subject matter is laid out well in some parts of the book, but Pollan jumps around a lot with the material, for instance, in chapter 15 he is foraging for food then chapter 16 is about a research article that gave him inspiration to write The Omnivore’s Dilemma, and then chapter 17 is about his moral conflict of eating steak at a steakhouse and whether or not the animal had to suffer to get to his plate. I think the book needs some improvement in this regard so the author is not jumping to different topics at random. In The Omnivore’s Dilemma, the author Michael Pollan is somewhat successful in satisfying the common expectations for the chapters I have read, one of the expectations is both a strength and a weakness for this part of the book. I think that the book as a whole does not satisfy the common expectations with the big one being engagement, there will be people who are interested in this book but it is only a small facet of the readers out there today. The book does deliver on the use of imagery and the subject matter stays on topic most of the time and supports his ideas and theories. Later on in part 3 in the next three chapters he goes on the hunt and he elaborates on the history of pigs that are not native to California and his feelings after the kill. He then finds some wild mushrooms to pair with the meat he has acquired from harvesting the pig and talks about his adventures trying to find non-poisonous mushrooms; and the final chapter presents the author preparing the meal with all of the components he has foraged for and harvested. Works Cited Pollan, M. (2006). The Omnivores Dilemma. New York, New York: Penguin Books.

Free Essays on The Adventures Of Tom Sawyer

The Adventures of Tom Sawyer â€Å"Boys will be boys,† is a quote that best describes Tom Sawyer, in Mark Twain’s The Adventures of Tom Sawyer. Tom is the typical American boy. He is always getting into something. Throughout the novel Tom matures into a young man. Tom was always a mischievous boy but he had a good heart. During a child’s adolescence he can mature from being a menace to a respectable man in society. Tom Sawyer was very immature at the beginning of the novel, but matured throughout his adventures. When Tom was in trouble and had to white wash his Aunt Polly’s fence, he used reverse psychology on his friends to make them want to do his work for him. Tom did not want to do the work, so he found a way to get someone to do it for him. This shows that he is smart, but that he is also very manipulative. Tom had an idol in one of his peers, Huckleberry Finn. Huck did whatever he wanted, whenever he wanted. He did not have to go to school, church or Sunday school if he did not want to. Tom and Huck became very good friends as the novel progressed. One night Tom and Huck decided to go to a graveyard to perform a ritual to get rid of warts, but they received more than they bargained for. The boys witnessed the murder of a young doctor that night. Injun Joe, the half-breed, was the murderer, however, he convinced Muff Potters, the town drunk, that he killed the young doctor. The boys are terrified by Injun Joe, so they made a pact not to say a word, â€Å"Huck Finn and Tom Sawyer swears they will keep mum about this and they wish they may fall down dead in their tracks if they ever tell and rot.† (Twain 70) Although this pact was made, Tom’s good or conscience comes into perspective. Tom cannot bear to let an innocent man hang. Tom breaks the pact with Huck and testifies in court. This shows great strength on Tom’s part. He went against his word, and risked facing Injun Joe. â€Å"When the half-... Free Essays on The Adventures Of Tom Sawyer Free Essays on The Adventures Of Tom Sawyer The Adventures of Tom Sawyer â€Å"Boys will be boys,† is a quote that best describes Tom Sawyer, in Mark Twain’s The Adventures of Tom Sawyer. Tom is the typical American boy. He is always getting into something. Throughout the novel Tom matures into a young man. Tom was always a mischievous boy but he had a good heart. During a child’s adolescence he can mature from being a menace to a respectable man in society. Tom Sawyer was very immature at the beginning of the novel, but matured throughout his adventures. When Tom was in trouble and had to white wash his Aunt Polly’s fence, he used reverse psychology on his friends to make them want to do his work for him. Tom did not want to do the work, so he found a way to get someone to do it for him. This shows that he is smart, but that he is also very manipulative. Tom had an idol in one of his peers, Huckleberry Finn. Huck did whatever he wanted, whenever he wanted. He did not have to go to school, church or Sunday school if he did not want to. Tom and Huck became very good friends as the novel progressed. One night Tom and Huck decided to go to a graveyard to perform a ritual to get rid of warts, but they received more than they bargained for. The boys witnessed the murder of a young doctor that night. Injun Joe, the half-breed, was the murderer, however, he convinced Muff Potters, the town drunk, that he killed the young doctor. The boys are terrified by Injun Joe, so they made a pact not to say a word, â€Å"Huck Finn and Tom Sawyer swears they will keep mum about this and they wish they may fall down dead in their tracks if they ever tell and rot.† (Twain 70) Although this pact was made, Tom’s good or conscience comes into perspective. Tom cannot bear to let an innocent man hang. Tom breaks the pact with Huck and testifies in court. This shows great strength on Tom’s part. He went against his word, and risked facing Injun Joe. â€Å"When the half-...

Transition to Democracy in Africa Essay Example | Topics and Well Written Essays - 1250 words

Transition to Democracy in Africa - Essay Example The first part analyzes the decisive transition to democracy by South Africa and the policies adopted by the country, and the second part examines the difficulties and challenges that hinder the transition to democracy for many African nations. Part 1 The decisive democratic transformation by South Africa has been a source of inspiration for civilization across the world. Only a few analysts predicted such radical progress, considering the bloody and long history of the country against apartheid. Indeed, majority of the experts expected the country to succumb to ethnic violence common in many African nations when repression begins to transform to revolution. Today, many parts of the African continent and across the world are experiencing civil wars, with international terrorism plugging both developing and developed world into a state of anarchy. There is need to design democratic preventive and resolution methods to create a peaceful world free from hatred, bitterness, wars, enmity, and oppression (Donaldson and Marais, 2002). The experiences by South Africa may provide some invaluable insights for transition to democracy for other countries. The apartheid regime responsible for the reign of terror for more than four decades and the subsequent incarceration of thousand of people is among the most ruthless and heartless regimes to ever occur since Hitler’s reign in Germany. This is why the peaceful transition to democracy by South Africa remains one of the most significant democratic transitions in the world. The racial prejudice and discrimination against the natives of the country began in 1652 with the first Europeans from Holland. The intensity of racial discrimination against the indigenous people, particularly the San and the Khoikhoi increased during the subsequent domination by the British and Dutch in Cape Colony. However, the Dutch established inland colonies, resulting to clashes with the British coastal colonies, and ultimately culminated to the Boer war between 1899 and 1902. Nevertheless, there was some power sharing between the British and the Dutch (now refereeing to themselves Afrikaners) until in 1940s when the Afrikaner National Party gained a stronger majority (Nathan, 2004). The African National Party institutionalized discrimination after coming into power in 1948. The strategists in the party invented apartheid to enable them cement their control over the social and economic system. The concept of apartheid was to ensure white dominance and extending racial separation. Thus, the â€Å"Grand Apartheid† plan was set in motion in the 1960s, focusing on police regression and territorial separation. The party enacted apartheid laws touching all aspects of life. With the assistance of the European Community and the United States, the pressure began on the South African President Botha to dismantle apartheid in 1980s. The end of 1991 saw the revoke of the legal apartheid framework. However, internal violence continued, but Nelson Mandela and F. W. de Klerk reached an agreement for the implementation of majority rule in 1993. Mandela was able to convince the United Nation to lift the remaining sanctions on the country.

Organizational Communcation Unit 7 Essay Example | Topics and Well Written Essays - 500 words

Organizational Communcation Unit 7 - Essay Example The major advantages of team work are; the team members can learn from each other and also assist others in their mission; more flexibility in work; new ideas and suggestion can be implemented; communication and cooperation among the employees can be improved; Greater autonomy and more freedom in work which will improve the productivity of the employees etc. The major disadvantages are; all the members of the team may not be compatible with the team functions; only specific workers can be included in the team; some members may get less motivating jobs which can increase the conflicts within the team; team functioning may take longer time because of the lack of coordination at the initial stages; Rewards and punishment may be less effective; less flexibility in transferring the workers from one place/ division to another etc. (Medsker, G.J.,& Campion, M.A) Group think is the process of decision making inside a group or a team. It occurs only when the group was highly cohesive and functions in a healthy manner. Group think has certain negative impacts on the team performances since it will not spend much time for finding out the exact solutions of a problem. Because of the strong cohesion group members will not analyse the ideas of others in a critical manner which will prevent them from identifying the real, future consequences of the decision. Expert opinions will never sought by a team functioning under groupthink. (Allyn & Bacon) I believe in democratic style of leadership. Autocratic approaches will never bring the desired results when we compare the long term goals of an organization. Democratic approach always helps the employees to feel more closeness towards the organization. They will consider the problems and the achievements of the organization as their own if we implement a democratic approach in management. But at the same time we must

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,