(+)-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

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Abstract

(+)-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.

Original languageEnglish
Pages (from-to)768-774
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number2
Publication statusPublished - 1996 May

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Nunoya, K. I., Yokoi, T., Kimura, K., Kodama, T., Funayama, M., Inoue, K., Nagashima, K., Funae, Y., Shimada, N., Green, C., & Kamataki, T. (1996). (+)-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. Journal of Pharmacology and Experimental Therapeutics, 277(2), 768-774.