[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.
Lou
Y Q
YQ
Department of Pharmacology, Beijing Medical University.
Kuang
T Y
TY
D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D008617:Mephenytoin / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin