EVIDENCE FOR THE EFFECT OF GENDER ON ACTIVITY OF (S)-MEPHENYTOIN 4'-HYDROXYLASE (CYP2C19) IN A CHINESE POPULATION

There is evidence that the sex-dependent expression of individual form s of the human cytochrome P450s (CYPs) results in gender-related diffe rences in the hepatic metabolism of certain drugs. Previous work has s hown that conflicting evidence exists relating to the sex differences in the activity of (S)-mephenytoin 4'-hydroxylase (CYP2C19). According ly, we assessed the effect of gender on CYP2C19 activity in a phenotyp ed and genotyped healthy unrelated Chinese population for further evid ence of such a gender-based differentiation. One hundred and sixteen f emales and 129 males took one tablet of 100 mg racemic mephenytoin (Me santoin, Sandoz) after emptying their urinary bladders. Amounts of (S) - and (R)-mephenytoin and its metabolite 4'-hydroxymephenytoin (4'-OH- M) excreted in the postdose 0-8 h urine collection were determined by GC and HPLC methods, respectively. The CYP2C19 activity was expressed as the ratio of S/R-mephenytoin (S/R-ratio), the percentage of the dos e excreted as 4'-OH-M (D%), and the log(10) of the hydroxylation index which was defined as the ratio of micromoles of (S)-mephenytoin dose to micromoles of 4'-OH-M excreted in urine (1g HI). From all the subje cts studied, 53 extensive metabolizers (EMs) and 19 poor metabolizers (PMs) phenotyped were randomly selected and the DNA extracted from the ir blood samples was utilized for genotyping analysis according to the previously developed standard procedures. In this population, the phe notype PMs were identified in 10.9% (14/128) of the males, as compared with 11.2% (13/116) of the females (chi(2) = 0.0045, df = 1; p > 0.05 ). In all phenotyped subjects, the S/R-ratio of EM males was significa ntly higher than that of EM females (mean +/- SD; 0.28 +/- 0.17 vs. 0. 24 +/- 0.15; p = 0.030), but no sexual differentiation was observed (p > 0.05) in 4'-OH-M excreted among all EMs and PMs, or the S/R-ratio a mong all PMs. In all genotyped EMs, the frequency of homozygous EMs wa s 18.4% higher in females (51.7%, 15/29) than in males (33.3%, 8/24) a lthough there was no significant difference (chi(2) = 1.1370, df = 1, p > 0.05), but the S/R-ratio was lower in homozygous females than in h omozygous males (0.22 +/- 0.14 vs. 0.33 +/- 0.09; p = 0.046). Thus, we conclude that the higher CYP2C19 activity in females exists among bot h the phenotyped EMs and the genotyped homozygous EMs compared with th at in males, and that the defect frequency of the enzyme activity is e qual between the genders. We also conclude that the S/R-ratio is more a sensitive metabolic marker of CYP2C19 enzyme activity than the D% an d lg HI.