In silico pharmacogenetics of warfarin metabolism

Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anti...

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Published inNature biotechnology Vol. 24; no. 5; pp. 531 - 536
Main Authors Peltz, Gary, Guo, Yingying, Weller, Paul, Farrell, Erin, Cheung, Paul, Fitch, Bill, Clark, Douglas, Wu, Shao-yong, Wang, Jianmei, Liao, Guochun, Zhang, Zhaomei, Allard, John, Cheng, Janet, Nguyen, Anh, Jiang, Sharon, Shafer, Steve, Usuka, Jonathan, Masjedizadeh, Mohammad
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.05.2006
Subjects
Animals
Biotransformation
Chromosome Mapping
Cytochrome P-450 Enzyme System - genetics
Drug therapy
Gene expression
Genetic Variation
Genetics
Haplotypes
Male
Metabolism
Mice
Mice, Inbred Strains
Pharmacogenetics - methods
Pharmacology
Protein Isoforms
Rodents
Species Specificity
Warfarin - metabolism
Warfarin - pharmacology
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Summary:Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.
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ISSN:1087-0156
1546-1696
DOI:10.1038/nbt1195