Stereoselectivity in bunitrolol 4-hydroxylation in liver microsomes from marmosets and Japanese monkeys

Shizuo Narimatsu, Masumi Gotoh, Yasuhiro Masubuchi, Toshiharu Horie, Shigeru Ohmori, Mitsukazu Kitada, Takashi Kageyama, Kazuo Asaoka, Ikuo Yamamoto, Tokuji Suzuki

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16 Citations (Scopus)

Abstract

The stereoselectivity in 4-hydroxylation of bunitrolol (BTL), a β- adrenoreceptor blocking agent, was examined in liver microsomes from monkeys (marmosets and Japanese monkeys) and compared with the results of human liver microsomes. The formation of (+)-4-OH-BTL from (+)-BTL was significantly higher than that of (-)-4-OH-BTL from (-)-BTL in the liver microsomal fractions from the two kinds of monkeys. The 4-OH-BTL-forming activity from racemic BTL was significantly lower than that from enantiomeric BTL, indicating a possible metabolic interaction between BTL enantiomers. The in vitro profiles observed in the monkeys were very similar to those in humans, but the stereoselectivity in BTL metabolism [(+)-BTL > (-)-BTL] in the primates was found to be reverse to that in rats [S. Narimatsu et al., Anal Biochem., 222, 256-261 (1994)]. The 4-OH-BTL-forming activity from BTL enantiomers was significantly suppressed by quinidine and quinine, while the former was more potent than the latter, and also by α-naphthoflavone. Furthermore, the activity was also suppressed by antisera against rat cytochromes P450-2D2 and -1A2 in concentration-dependent manners. However, kinetics showed that enantiomeric BTL 4-hydroxylation was monophasic in liver microsomes from marmosets of both genders and from male Japanese monkeys. These results suggest that cytochrome P450-2D and -1A enzymes with similar K(m) values are involved in BTL 4-hydroxylation in monkey liver microsomes.

Original languageEnglish
Pages (from-to)1429-1433
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume19
Issue number11
DOIs
Publication statusPublished - Nov 1996

Keywords

  • Japanese monkey
  • bunitrolol 4- hydroxylation
  • cytochrome P450-2D, -1A
  • human liver microsome
  • marmoset
  • stereoselectivity

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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