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Pharmacogenet Genomics. 2005 Jul;15(7):475-81.

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

Author information

1
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.

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.

[Indexed for MEDLINE]

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