Contribution of Flavin-Containing Monooxygenase and Cytochrome P450 to Imipramine N-Oxidation in Rat Hepatic Microsomes

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Enzymatic formation of desipramine (DMI) and imipramine N-oxide (IMINO) was kinetically characterized in rat liver microsomes at pH 8.5 and 7.5 The formation of IMINO was quickly suppressed by the preincubation of microsomes at 37℃ at pH 8.5,but the suppression was comparatively gentle at pH 7.5. In kinetic sutdies, the formation of DMI was monophasic at the two pH Points, and a substrate inhibition was observed at pH 8.5,but not at pH 7.5. In contrast, the formation of IMINO was biphasic at both pH points, i.e., the summation of a low-K_m phase and a high-K_m phase. Methimazole (MZ), an inhibitor of flavin-containing monooxygenase (FMO), markedly suppressed the low-K_m phase of IMINO formation at both pH points. MZ also suppressed DMI formation at pH 8.5,but it elevated DMI formation at pH 7.5 SKF 525-A, an inhibitor of cytochrome P450 (CYP), markedly suppressed DMI formation at both pH points. The inhibitor suppressed IMINO formation in the high-K_m phase of the biphasic kinetics at both pH points, whereas it stimulated the activity of the low-K_m phase at pH7.5. These results suggest that CYP enzyme(s) are mainly reponsible for DMI formation at pH 8.5 and 7.5,and FMO enzyme(s) also are involved in IMI N-demethylation at a higher pH range in rat liver microsomes, at least in part. In the formation of IMINO, FMO is a major enzyme at both pH points, and CYP may also contribute to the N-oxide formation to some extent at pH 8.5.
公益社団法人日本薬学会の論文
1999-06-15

Contribution of Flavin-Containing Monooxygenase and Cytochrome P450 to Imipramine N-Oxidation in Rat Hepatic Microsomes

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