Genetic Polymorphism of Cytochrome P450 2C19

Abstract

The measurement of S-mephenytoin hydroxylation was an original method for studying CYP2C19 polymorphism. This led to discover that CYP2C19 polymorphism in human is mediated through an autosomal recessive trait. The prevalence of this polymorphism exhibits a wide interethnic variation ranging from 1-6% of poor metabolizer (PM) in Caucasians to more than 40% in some Pacific islanders. At least 11 CYP2C19 allellic variants have been described. Except for the wild-type allelles (CYP2C19*1 or CYP2C19wt), all other mutant allelles led to either abolish or decrease CYP2C19 activity. The mutant allelles CYP2C19*2 and CYP2C19*3 were found to cover almost all of the PM in Asian populations, but to a lesser extent when applied to Caucasians. As CYP2C19 is responsible for metabolism of many currently used medications, individual CYP2C19 alteration would lead to increasing risk of either therapeutic failures or misadventures. The urinary mephenyotin S/R ratio has successfully been used for phenotyping CYP2C19 by several investigators, but concerns regarding adverse drug effect, analysis difficulty and long term sample unstability have limited its utility. The proguanil/cycloguanil ratio has been used for CYP2C19 expression, but overlapping result between the (PM) and (EM) also limits its utility. The plasma omeprazole/5-hydroxyomeprazole ratio correlates well with CYP2C19 genotype and has led to another substrate probe studied with advantages including less side effects and less difficulties in drug quantitation. Genotyping of CYP2C19 can be determined by the PCR-RFLP techniques. After digestion with appropriate restriction endonucleases, the pattern of CYP2C19 allelles can be simply revealed under the agarose electrophoresis. To date only a few studies have been reported on CYP2C19 polymorphism in Thai population. The discrepancy in finding of PM between 7% and 18% warrants further investigation before any unambiguous conclusion can be made.