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National Institute of Environmental Health Sciences

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Publication Detail

Title: In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose.

Authors: Tai, Guoying; Farin, Frederico; Rieder, Mark J; Dreisbach, Albert W; Veenstra, David L; Verlinde, Christophe L M J; Rettie, Allan E

Published In Pharmacogenet Genomics, (2005 Jul)

Abstract: OBJECTIVE: To determine the in-vitro and in-vivo effects of the CYP2C9*11 polymorphism on (S)-warfarin metabolism. METHODS AND RESULTS: The *11 allele that results in mutation of Arg335-->Trp occurred with a frequency of approximately 1% in Caucasian and African-American populations. Four subjects carrying the *1/*11 genotype were identified in a clinical cohort of 192 warfarin patients. Compared to control subjects with the *1/*11 genotype (n=127), the *1/*11 group exhibited a 33% reduction in warfarin maintenance dose, that was independent of study population age or INR. In-vitro studies directed towards understanding the mechanism of reduced in-vivo activity revealed very low levels of holo-CYP2C9.11 expression in insect cells and decreased solubility in the presence of detergent. Membrane preparations of CYP2C9.11 contained inactive P420 and exhibited a shorter half-life for thermally induced conversion of P450 to P420 than CYP2C9.1. Metabolic studies demonstrated that functional CYP2C9.11 possessed similar (S)-warfarin hydroxylation regioselectivity and modestly reduced catalytic efficiency relative to the wild-type enzyme. CONCLUSIONS: In-vivo reduction in CYP2C9 (S)-warfarin activity due to the CYP2C9*11 polymorphism may largely be a consequence of decreased enzyme stability resulting in compromised expression of holo-enzyme. Increased enzyme lability of CYP2C9.11 may be related to improper folding due to the disruption of conserved salt-bridge and hydrogen bonding contacts in the loop region between the J and J' helices of the protein.

PubMed ID: 15970795 Exiting the NIEHS site

MeSH Terms: Anticoagulants/metabolism*; Aryl Hydrocarbon Hydroxylases/chemistry; Aryl Hydrocarbon Hydroxylases/genetics; Aryl Hydrocarbon Hydroxylases/metabolism*; Dose-Response Relationship, Drug; European Continental Ancestry Group/genetics*; Female; Genotype; Humans; Hydroxylation; In Vitro; Japan; Linkage Disequilibrium; Male; Metabolic Clearance Rate; Middle Aged; Mutagenesis, Site-Directed; NADPH-Ferrihemoprotein Reductase/metabolism*; Polymerase Chain Reaction; Polymorphism, Genetic*; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.; Temperature; Warfarin/metabolism*

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