Species differences in stereoselective metabolism of mephenytoin by cytochrome P450 (CYP2C and CYP3A).
Stereoselective involvement of hepatic cytochrome P450 in the metabolism of mephenytoin was investigated in vitro by using livers of five different experimental animal species and humans. The rates of microsomal 4'-hydroxylation were 2 to 6 times higher with the R-enantiomer than the S-enantiomer in rabbits, dogs and rats, whereas the rates of the 4'-hydroxylation in female mice were not different between R- and S-enantiomers. Preferential S-mephenytoin 4'-hydroxylation was observed in monkeys as similar to that in humans. The rates of microsomal mephenytoin N-demethylation were approximately 2 times higher with the R-enantiomer than the S-enantiomer in male rats and both sexes of dogs. Antibodies raised against CYP2C11 (anti-CYP2C) clearly inhibited microsomal 4'-hydroxylation of S-mephenytoin and N-demethylation of R-mephenytoin in rats, monkeys and humans. Antibodies raised against CYP3A2 (anti-CYP3A) clearly inhibited microsomal 4'-hydroxylation of R-mephenytoin, but marginally S-mephenytoin, in rats. Anti-CYP3A, however, showed no clear inhibition on microsomal 4'-hydroxylation and N-demethylation of both enantiomers in monkeys and humans, except for slight inhibition of R-mephenytoin 4'-hydroxylation in male monkeys. The results suggest that stereoselective involvement of rat CYP3A and scant involvement of human CYP3A in R-mephenytoin 4'-hydroxylation are major determinants of the species differences between rats and humans in stereoselective mephenytoin 4'-hydroxylation.
Yasumori
T
T
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Chen
L
L
Nagata
K
K
Yamazoe
Y
Y
Kato
R
R
D000328:Adult; D000368:Aged; D000818:Animals; D000906:Antibodies; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008252:Macaca fascicularis; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013237:Stereoisomerism
D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008617:Mephenytoin