Large inter-individual variation in the oxidative metabolism of warfarin and losartan among CYP2C9*1/*1 individuals led investigators to question whether or not regulatory polymorphisms affecting CYP2C9 expression might exist. Although a considerable amount of information is known regarding the CYP2C9 haplotype structure and in vitro evidence for functional CYP2C9 regulatory polymorphisms has been reported, there have been no reports providing direct evidence for the functional significance of regulatory polymorphisms in vivo. In this issue, Chaudhry et al., demonstrate that the previously reported CYP2C9*1B haplotype is associated with a decreased phenytoin maintenance dose in epileptic patients. The impetus for their study was the observation that individuals homozygous for CYP2C9*1, but heterozygous for CYP2C19*2, exhibited a mean 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) S/R ratio of only 12.9. This observation was unexpected because phenytoin is metabolized to p-HPPH primarily by CYP2C9 (90%) and secondarily by CYP2C19, and in contrast to the latter enzyme, CYP2C9 exhibits high prochiral stereoselectivity (p-HPPH S/R ratio of 43-44). Based on this observation, the authors hypothesized a hypomorphic CYP2C9 variant haplotype in linkage disequilibrium with CYP2C19*2. Consistent with this hypothesis, the authors discovered that the previously described CYP2C9*1B haplotype is in linkage disequilibrium with the CYP2C19*2 allele and explained that as much as 10% of the variation in phenytoin maintenance dose was found in epileptic patients, an effect size comparable to that observed for the CYP2C9*2 and CYP2C9*3 hypomorphic alleles. Because there was no association with warfarin dose requirements in another patient cohort or with the phenytoin metabolic ratio in human liver microsomes, the authors further hypothesized that CYP2C9*1B affected pregnane X receptor (PXR; NR1I2)-dependent CYP2C9 induction by phenytoin. Based on sequence analysis, the mechanism appeared to be the creation of a YY1 recognition element with the −3089GA SNP and destruction of a Nrf2 recognition element with the −2663delTG SNP. This proposed mechanism was consistent with transient transfection studies employing CYP2C9 reporter constructs and PXR, Nrf2, and YY1 expression vectors. Thus, any proposed use of pharmacogenetic-based algorithms to optimize phenytoin dosing in epilepsy patients should not only include an assessment of CYP2C9*2, *3 but also CYP2C9*1B. These results also may be relevant to the clinical use of other PXR, constitutive androstane receptor, or Nrf2 activators when CYP2C9 is a determinant of drug disposition or response.
See article at J Pharmacol Exp Ther 2010, 332:599–611.
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