Analysis of human interindividual and racial differeness of drug response and metabolism : Approach by the method of diagnosis by gene analysis

点击翻译按钮获取中文摘要

Mephenytoin was administered to seven healthy volunteers of Japanese, and those were phenotyped extensive(EM)and poor metabolizers(PM)of mephenytoin 4'-hydroxylation.Six subjects were judged as EM,and one as PM.Twelve liver microsomal samples of Japanese and five samples of Caucasian were also phenotyped EM and PM by measuring R-and S-mephenytoin 4'-hydroxylation.Nine Japanese and five Caucasian subjects were judged as EM and three Japanese were PM.Genomic DNAs were isolated from nine EM and four PM,and DNA sequences were analyzed and the sequences of putative mephenytoin 4'-hydroxylases (CYP2C forms) were compared between EM and PM.No difference was observed on the sequences of CYP2C9/18 between EM and PM.Anucleotide substitution was detected in the sequence of exon 4 of CYP2C19 in PM,phenotyped in vivo.Another mutation was detected in the sequense of intron 4 just before exon 5 of CYP2C19 in PM,phenotyped in vitro.In either case, CYP2C19 does not express in PM livers, Metabolism of diazepam was studied in vitro by using liver microsomes obtained from EM and PM.The rate of diazepam N-demethylation was about one-third that of 3-hydoxylation at a high substrate concentration(0.2mM), however, the rate of N-demethylation increases with the decrease in the substrate concentration (-0.02mM).Diazepam N-demethylation seems to be mediated by CYP2C forms.On the other hand, diazepam 3-hydroxylation was selectively catalyzed by CYP3A forms.These results were consistent with the observation in vivo that diazepam N-demethylation and S-mephenytoin 4'-hydroxylation are closely correlated in humans.