[The molecular mechanism of polymorphism of S-mephenytoin hydroxylative metabolism]

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 P450 UK was purified and identified to be CYP 2C19 by amino-terminal amino acid analyses. The levels of P450 2C19 and the ability of the human liver samples to 4'-hydroxylate S-mephenytoin 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 2C19 resulting in an aberrantly spliced mRNA and a non-functional P450 2C19 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 2C19) also affects metabolism of several other widely clinical used drugs.