Allelic Variants of Human Cytochrome P450 2C9: Baculovirus-Mediated Expression, Purification, Structural Characterization, Substrate Stereoselectivity, and Prochiral Selectivity of the Wild-Type and I359L Mutant Forms

Haining, Robert L.; Hunter, Ann P.; Veronese, Maurice E.; Trager, William; Rettie, Allan E.

doi:10.1006/abbi.1996.0414

Cited by 232 publications

(127 citation statements)

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“…Compared with extensive metabolizers, who are homozygous for the wild-type *1 allele, homozygosity for *2 reduces CYP2C9 enzyme activity to 12% whereas homozygosity for *3 reduces enzyme activity to 5%. [29][30][31] In accordance with this, many studies have shown that patients with the CYP2C9*2 and CYP2C9*3 variant alleles require lower mean daily warfarin doses ( Table 2). [1][2][3][5][6][7][8][32][33][34][35][36][37][38] A systematic review and meta-analysis of nine studies has established that the CYP2C9*2 and CYP2C9*3 alleles lead to 17 and 37% reduction in the daily warfarin dose, respectively.…”

Section: Biotransformation Of Warfarinmentioning

confidence: 58%

Pharmacogenetics of warfarin: current status and future challenges

2006

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Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P 450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

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Section: Biotransformation Of Warfarinmentioning

confidence: 58%

Pharmacogenetics of warfarin: current status and future challenges

2006

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“…Genetic polymorphisms of CYP2C9 include more than 34 alleles (41). Alleles CYP2C9*2, *3, *4,*5, and *30 have aminoacid replacement, and have been reported to reduce in vitro (107,108) and/or in vivo catalityc activities (108,109,110).…”

Section: Cyp2c9mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

167

111

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The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

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“…Alleles CYP2C9*2, *3, *4 and *5 lead to amino acid replacements, and these mutations have been shown to decrease catalytic activities in vitro (Rettie et al, 1994;Haining et al, 1996;Sullivan-Klose et al, 1996;Dickmann et al, 2001;Kidd et al, 2001;Takahashi et al, 2004). CYP2C9*3 is reported to lead to lower activities in vivo (Sullivan-Klose et al, 1996;Shintani et al, 2001;Takahashi et al, 2004).…”

Section: (I)mentioning

confidence: 99%

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

Hellou¹,

Beach²,

Leonard³

et al. 2012

Polycyclic Aromatic Compounds

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initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, life-style factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in chemical carcinogenesis Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications -whether for sale or for noncommercial distribution -should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: permissions@who.int).The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data NOTE TO THE READERThe term 'carcinogenic risk' in the IARC Monographs series is taken to mean that an agent is capable of causing cancer under some circumstances. The Monographs evaluate cancer hazards, despite the historical presence of the word 'risks' in the title.Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that it is not carcinogenic.The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No recommendation is given for regulation or legislation.Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information available to the Section of IARC Monographs, International Agency for...

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Allelic Variants of Human Cytochrome P450 2C9: Baculovirus-Mediated Expression, Purification, Structural Characterization, Substrate Stereoselectivity, and Prochiral Selectivity of the Wild-Type and I359L Mutant Forms

Cited by 232 publications

References 0 publications

Pharmacogenetics of warfarin: current status and future challenges

Pharmacogenetics of warfarin: current status and future challenges

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

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