Ohmori S, Takeda S, Rikihisa T, Kiuchi M, Kanakubo Y, Kitada M
Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Biol Pharm Bull. 1993 Jun;16(6):571-5. doi: 10.1248/bpb.16.571.
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.
丙咪嗪2 - 羟化酶的活性与去甲丙咪嗪2 - 羟化酶的活性高度相关，但与去甲丙咪嗪N - 脱甲基酶的活性无关。当以丙咪嗪为底物时，还发现N - 脱甲基作用与2 - 羟化作用之间存在相关性，而当用去甲丙咪嗪代替丙咪嗪时，未观察到它们之间的相关性。奎尼丁可显著抑制去甲丙咪嗪和丙咪嗪2 - 羟化酶的活性，但奎宁可不会。虽然丙咪嗪N - 脱甲基酶的活性受到奎尼丁和奎宁的轻微抑制，但在相同条件下去甲丙咪嗪N - 脱甲基酶的活性未受影响。丙咪嗪N - 脱甲基酶的活性与免疫化学测定的P450 3A4量以及人肝微粒体中睾酮6β - 羟化酶的活性大致相关。在重组系统中，P450 3A4催化丙咪嗪N - 脱甲基作用比2 - 羟化作用更有效，而去甲丙咪嗪的N - 脱甲基作用和2 - 羟化作用均未被P450 3A4催化。人肝微粒体中的抗P450 3A4抗体在不同程度上抑制了丙咪嗪N - 脱甲基酶的活性。综合这些及其他结果表明，除P450 2Cmp外，P450 3A4也部分参与了人肝微粒体中丙咪嗪的N - 脱甲基作用。
