Studies on cytochrome P450 responsible for oxidative metabolism of imipramine in human liver microsomes.
The activity of imipramine 2-hydroxylase highly correlated with that of desipramine 2-hydroxylase but not with that of desipramine N-demethylase. The correlation was also found between N-demethylation and 2-hydroxylation when imipramine was used as a substrate, whereas no correlation was observed between them when desipramine was used in place of imipramine. Both activities of desipramine and imipramine 2-hydroxylase were markedly inhibited by quinidine but not by quinine. Although the activity of imipramine N-demethylase was slightly inhibited by both quinidine and quinine, the activity of desipramine N-demethylase was unaffected under the same conditions. The activity of imipramine N-demethylase was roughly correlated with the amounts of P450 3A4 immunochemically determined and the activities of testosterone 6 beta-hydroxylase in human liver microsomes. The P450 3A4 catalyzed imipramine N-demethylation much more efficiently than 2-hydroxylation in a reconstituted system, whereas neither N-demethylation nor 2-hydroxylation of desipramine was catalyzed by P450 3A4. The activity of imipramine N-demethylase was inhibited, to various extents, by anti-P450 3A4 antibodies in human liver microsomes. Taking together these and other results, it is suggested that P450 3A4, other than P450 2Cmp, also partly contributes to N-demethylation of imipramine, depending on human liver microsomes.
Ohmori
S
S
Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Takeda
S
S
Rikihisa
T
T
Kiuchi
M
M
Kanakubo
Y
Y
Kitada
M
M
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D003891:Desipramine / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007099:Imipramine / Q000378:metabolism*; D015151:Immunoblotting; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D011803:Quinine; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D010089:Oxidoreductases, N-Demethylating; C082995:desipramine N-demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D011802:Quinidine; D007099:Imipramine; D003891:Desipramine