(+)-Cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502) as a novel substrate for cytochrome P450 2A6 in human liver microsomes 1

Ken Ichi Nunoya, Tsuyoshi Yokoi, Kanzo Kimura, Takao Kodama, Masato Funayama, Kazuaki Inoue, Kazuo Nagashima, Yoshihiko Funae, Noriaki Shimada, Carol Green, Tetsuya Kamataki

研究成果: Article査読

56 被引用数 (Scopus)

抄録

(+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) was oxidized by human liver microsomes to produce the S-oxide as a sole metabolite. Indirect evidence suggested that the S-oxidation was catalyzed by cytochrome P450 (CYP). Eadie-Hofstee plots showed biphasic pattern, suggesting that at least two enzymes were involved in the S-oxidation in human liver microsomes. Kinetic parameters of the S-oxidase with high-affinity showed Km and Vmax values of 20.9 ± 4.4 μM and 0.111 ± 0.051 nmol/min/mg microsomal protein, respectively. The S-oxidase activity was inhibited by coumarin and anti-CYP2A antibody. Among the contents of forms of CYP in 20 samples of human liver microsomes, the content of CYP2A6 correlated with S-oxidase activity measured with 50 μM SM-12502 (r = .808, P < .0005). A close correlation (r = .908, P < .0001) was observed between activities of SM-12502 S-oxidase and coumarin 7-hydroxylase. Microsomes from genetically engineered human B-lymphoblastoid cells expressing CYP2A6 metabolized SM-12502 to the S-oxide efficiently. The results indicate that CYP2A6 isozyme is a major form of CYP responsible for the S-oxidation of SM-12502 in human liver micosomes. Thus, SM-12502 will be a useful tool in further research to analyze a human genetic polymorphism of CYP2A6.

本文言語English
ページ(範囲)768-774
ページ数7
ジャーナルJournal of Pharmacology and Experimental Therapeutics
277
2
出版ステータスPublished - 1996 5
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 薬理学

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