Contribution of flavin-containing monooxygenase and cytochrome P450 to imipramine N-oxidation in rat hepatic microsomes

Biol Pharm Bull. 1999 Jun;22(6):567-71. doi: 10.1248/bpb.22.567.

Abstract

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 degrees C at pH 8.5, but the suppression was comparatively gentle at pH 7.5. In kinetic studies, 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, Le., the summation of a low-Km phase and a high-Km phase. Methimazole (MZ), an inhibitor of flavin-containing monooxygenase (FMO), markedly suppressed the low-Km 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-Km phase of the biphasic kinetics at both pH points, whereas it stimulated the activity of the low-Km phase at pH 7.5. These results suggest that CYP enzyme(s) are mainly responsible 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.

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / metabolism*
  • Cytochrome P-450 Enzyme System / physiology*
  • Drug Combinations
  • Drugs, Chinese Herbal / pharmacology
  • Hydrogen-Ion Concentration
  • Imipramine / metabolism*
  • Kinetics
  • Male
  • Microsomes, Liver / metabolism*
  • Oxidation-Reduction
  • Oxygenases / physiology*
  • Rats
  • Rats, Wistar

Substances

  • Antidepressive Agents, Tricyclic
  • Drug Combinations
  • Drugs, Chinese Herbal
  • shakuyaku-kanzoh-toh
  • Cytochrome P-450 Enzyme System
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Imipramine