Studies on structure, function and regulation mechanism of drug-metabolizing enzymes

Researcher : Yorishige Imamura

　We have so far provided significant information regarding the structure, function and regulation mechanism of drug-metabolizing enzymes, especially carbonyl reductase. The main purpose of recent works is to elucidate the structure and function of a tetrameric carbonyl reductase purified from pig heart. This enzyme contains a peroxisomal tergeting signal type-1 (PTS1) as the C-terminal tripeptide (SRL). We are currently investigating the molecular mechanism for peroxisomal import of the tetrameric enzyme.

Research topics

1. Structure and function of carbonyl reductase

2. Regulation mechanism for carbonyl reductase

3. Transportation mechanism for peroxisomal carbonyl reductase

References（２０００〜）

Oginuma M, Shimada H, Imamura Y. Involvement of carbonyl reductase in superoxide formation through redox cycling of adrenochrome and 9,10-phenanthrenequinone in pig heart. Chem.-Biol. Interact. 155:148-154 (2005).

Shimada H, Uchida M, Okawara T, Abe S-I, Imamura Y. Inhibitory effects of flavonoids on the reduction of progesterone to 20alpha-hydroxyprogesterone in rat liver. J. Steroid Biochem. Mol. Biol. 93:73-79 (2005).

Imamura Y, Shimada H. Differential pharmacokinetics of acetohexamide in male Wistar-Imamichi and Sprague-Dawley rats: role of microsomal carbonyl reductase. Biol. Pharm. Bull. 28:185-187 (2005).

Imamura Y, Shimada H. Strain- and sex-related differences of carbonyl reductase activities in kidney microsomes and cytosol of rats. J. Appl. Toxicol. 24:437-441 (2004).

Shimada H, Oginuma M, Hara A, Imamura Y. 9,10-Phenanthrenequinone, a component of diesel exhaust particles, inhibits the reduction of 4-benzoylpyridine and all-trans-retinal and mediates superoxide formation through its redox cycling in pig heart. Chem. Res. Toxicol. 17:1145-1150 (2004).

Imamura Y, Noda A, Imamura T, Ono Y, Okawara T, Noda H. A novel methylthio metabolite of s-triazolo[3,4-a]phthalazine, a lead compound for the development of antianxietic drugs, in rats. Life Sci. 74: 29-36 (2003).

Shimada H, Fujiki S, Oginuma, M, Asakawa M, Okawara T, Kato K, Yamamura S, Akita H, Hara A, Imamura Y. Stereoselective reduction of 4-benzoylpyridine by recombinant pig heart carbonyl reductase. J. Mol. Catal. B: Enzym. 23: 29-35 (2003).

Usami N, Ishikura S, Abe H, Nagano M, Uebuchi M, Kuniyasu A, Otagiri M, Nakayama H, Imamura Y, Hara A. Cloning, expression and tissue distribution of a tetrameric form of pig carbonyl reductase. Chem.-Biol. Interact. 143-144: 353-361 (2003).

Shimada H, Imamura Y. Carbonyl reductase and its application. Kagaku Kogyo (Chemical Industry) 54: 98-104. Review (2003).

Imamura Y, Koga T, Shimada H, Otagiri M. Inactivation of rabbit liver carbonyl reductase by phenylglyoxal and 2,3,4-trinitrobenzenesulfonate sodium. J. Enzyme Inhib. Med. Chem. 18: 35-39 (2003).

Imamura Y, Kaneko M, Takada H, Otagiri M, Shimada H, Akita H. Sex-dependent pharmacokinetics of S(-)-hydroxyhexamide, a pharmacologically active metabolite of acetohexamide, in rats. Comp. Biochem. Physiol. Part C 133: 587-592 (2002).

Imamura Y, Takada H, Kamizono R, Otagiri M. Differential hormonal regulation of carbonyl reductase activities in liver and kidney microsomes of rats. Xenobiotica 32: 729-737 (2002).

Imamura Y, Wu X, Noda A, Noda H. Side-chain metabolism of propranolol: involvement of monoamine oxidase and mitochondrial aldehyde dehydrogenase in the metabolism of N-desisopropylpropranolol to naphthoxylactic acid in rat liver. Life Sci. 70: 2687-2697 (2002).

Imamura Y, Higuchi T, Otagiri M. Protective effects of suprofen and its methyl ester against inactivation of rabbit kidney carbonyl reductase by phenylglyoxal. J. Enzyme Inhib. 16: 451-455 (2001).

Imamura Y, Takada H, Kamizono R, Otagiri M. Hormonal regulation of male-specific 20beta-hydroxysteroid dehydrogenase with carbonyl reductase-like activity present in kidney microsomes of rats. J. Steroid Biochem. Mol. Biol. 78: 373-378 (2001).

Imamura Y, Sanai K, Seri K, Akita H. Hypoglycemic effect of S(-)-hydroxyhexamide, a major metabolite of acetohexamide, and its enantiomer R(+)-hydroxyhexamide. Life Sci. 69: 1947-1955 (2001).

Wu X, Noda A, Noda H, Imamura Y. Side-chain metabolism of propranolol: involvement of monoamine oxidase and aldehyde reductase in the metabolism of N-desisopropylpropranolol to propranolol glycol in rat liver. Comp. Biochem. Physiol. Part C 129: 361-368 (2001).

Imamura Y, Uchida A, Takada H, Otagiri M, Tsuchiya K. Strain-, sex- and species-related differences of acetohexamide reductase and 20beta-hydroxysteroid dehydrogenase activities in liver microsomes of experimental animals. Yakugaku Zasshi 121: 85-91 (2001).

Takada H, Uchida A, Kamizono R, Otagiri M, Imamura Y. Further studies on 20beta-hydroxysteroid dehydrogenase with carbonyl reductase-like activity present in liver microsomes of male rats. Life Sci. 67: 2075-2082 (2000).

Imamura Y, Migita T, Uriu Y, Otagiri M, Okawara T. Inhibitory effects of flavonoids on rabbit heart carbonyl reductase. J. Biochem. 127: 653-658 (2000).

Seri K, Sanai K, Kurashima K, Imamura Y, Akita H. (R)-ACX is a novel sulfonylurea compound with potent, quick and short-lasting hypoglycemic activities. Eur. J. Pharmacol. 389: 253-256 (2000).

Imamura Y, Koga T, Uriu Y, Otagiri M, Satoh K, Hara A. Catalytic properties for naphthoquinones and partial primary structure of rabbit heart acetohexamide reductase. Biol. Pharm. Bull. 23: 155-158 (2000).