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The Molecular Mechanism of Polymorphism of S-mephenytoin Hydroxylative Metabolism

LOU Ya-Qing;KUANG Tang-Yong(Deportment of Pharmacology, Beijing Medical University, Beijing 100083)  
The hydroxylation of S-mephenytoin exhibits a genetic polymorphism in humans and there are a large interethnic differences in the frequency of the poor metabolizer phenotype.A S-mephenytoin P450-hydroxylase termed P4 50 UK was purified and identified to be CYP 2C 19 by amino-terminal amino acid analyses.The levels of P450 2C19 and the ability of the human liver samples to 4'-hydroxylate Smephenytoin were found to be strongly correlative.Recent report showed that the principle defect in S-mephenytoin poor metabolizers is a single base pair(G→A)mutation in exon 5 of CYP 2C 19 resulting in an aberrantly spliced mRNA and a non-functional P450 2C 19 protein in liver of S-mephenytoin PM.Further investigations demonstrate that this major defect is responsible for about 75% of poor metabolizer phenotype in both caucasians and orientals who are homozygous for S-mephenytoin hydroxylation defect.This genetic defect(CYP 2C 19)also affects metabolism of several other widely clinical used drugs.
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