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

Shizuo Narimatsu, Shigeo Yamamoto, Rika Kato, Yasuhiro Masubuchi, Toshiharu Horie

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 °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, 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 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.

Original languageEnglish
Pages (from-to)567-571
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume22
Issue number6
DOIs
Publication statusPublished - Jun 1999

Keywords

  • Cytochrome P450
  • Enzyme kinetics
  • Flavin-containing monooxygenase
  • Methimazole
  • Rat liver microsome
  • SKF 525-A

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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