Hepatic metabolism of tolbutamide: characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition.
In vitro investigations suggest the same human liver cytochrome P-450 that catalyzes S-mephenytoin 4-hydroxylation, P-450MP, is responsible for methyl hydroxylation of the oral hypoglycemic agent tolbutamide. Tolbutamide hydroxylase activity copurified with P-450MP; electrophoretically homogenous P-450MP catalyzed both tolbutamide and S-mephenytoin hydroxylation. Each substrate competitively inhibited hydroxylation of the other, and anti-P-450MP inhibited tolbutamide hydroxylation in human liver microsomes. Significant correlation between tolbutamide and S-mephenytoin hydroxylase activities was seen in a set of human liver samples. These findings suggested that subjects with a genetically determined impairment in ability to hydroxylate mephenytoin might also have deficient tolbutamide metabolism. However, plasma tolbutamide concentration-time profiles and urinary excretion of metabolites formed via the hydroxylation pathway were similar in four phenotypically poor and six extensive metabolizers of mephenytoin. We suggest that alteration of a substrate binding site of P-450MP may reduce its ability to hydroxylate S-mephenytoin but not tolbutamide.
D000328:Adult; D000368:Aged; D001667:Binding, Competitive; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D014044:Tolbutamide / Q000378:metabolism*
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D008617:Mephenytoin