Stereoselectivity in Bunitrolol 4-Hydroxylation in Liver Microsomes from Marmosets and Japanese Monkeys

• Published in: Biological & pharmaceutical bulletin 1996/11/15, Vol.19(11), pp.1429-1433
• Main Authors: NARIMATSU, Shizuo, GOTOH, Masumi, MASUBUCHI, Yasuhiro, HORIE, Toshiharu, OHMORI, Shigeru, KITADA, Mitsukazu, KAGEYAMA, Takashi, ASAOKA, Kazuo, YAMAMOTO, Ikuo, SUZUKI, Tokuji
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - metabolism; Animals; Antiarythmic agents; Biological and medical sciences; bunitrolol 4-hydroxylation; Callithrix; Cardiovascular system; Cytochrome P-450 Enzyme System - analysis; Cytochrome P-450 Enzyme System - physiology; cytochrome P450-2D, -1A; Cytochromes b5 - analysis; Female; human liver microsome; Humans; Hydroxylation; Immunoblotting; Japanese monkey; Macaca; Male; marmoset; Medical sciences; Microsomes, Liver - metabolism; Pharmacology. Drug treatments; Propanolamines - metabolism; Stereoisomerism; stereoselectivity
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.19.1429

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 recemic 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. Narimatus 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 Km values are involved in BTL 4-hydroxylation in monkey liver microsomes.