Mechanism of molecular multiplicity and genetic deficiency of carbonyl reductase functioning as a drug-metabolizing enzyme

羰基还原酶作为药物代谢酶的分子多样性和遗传缺陷机制

• 批准号: 08672515
• 负责人: IMAMURA Yorishige
• 金额: $ 1.41万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672515/
• 关键词: drug-metabolizing enzyme; molecular multiplicity; genetic deficiency; carbonyl reductase; rat liver microsomes; acetohexamide; 20βーヒドロキシステロイド デヒドロゲナーゼ; 遺伝子様式

The mechanism of molecular multiplicity and genetic deficiency of carbonly reductase functioning as a drug-metabolizing enzyme has been examined. The obtained results are as follows :1.An enzyme was partially purified from liver microsomes of male rats by using metyrapone as a substrate. The partially purified metyrapone reductase had no ability to reduce acetohexamide. These results indicate that the ketone-reduction of metyrapone and acetohexamide can be catalyzed by different carbonyl reductases.2.1)A marked strain- and sex-related differences were observed in acetohexamide reductase activity in liver microsomes of rats. However, there was no strain- or sex-related difference of acetohexamide reductase activity in liver cytosol of rats. 2)Treatment with cadmium indirectly decreased acetohexamide reductase activity, which is regulated by androgens, in kidney microsomes of male rats. On the other hand, Cd treatment had no significant effect on acetohexamide reductase activity in kidney cytosol of male rats. The results described in 1)and 2)suggest multiplicity of carbonyl reductase present in rat liver and kidney.3.A simple Mendelian genetic analysis for the frequency distribution of acetohexamide reductase activity in liver microsomes of male rats provides evidence that the phenotype is genetically regulated by an autosomal co-dominant fashion. Female rats, unlike male rats, did not exhibit microsomal enzyme activity in parental, first filial and second filial generations. Based on these results, it is concluded that the inheritance of the microsomal enzyme activity is sex-limited.Further studies are in progress to elucidate the mechanism of genetic deficiency of acetohexamide reductase activity in liver microsomes of male rats.

研究了作为药物代谢酶的碳还原酶的分子多样性和遗传缺陷的机制。结果如下：1.以甲吡酮为底物，从雄性大鼠肝微粒体中部分纯化出一种酶。部分纯化的甲吡酮还原酶没有能力还原醋磺己脲。这些结果表明，甲吡酮和醋磺己脲的酮还原反应可以由不同的羰基还原酶催化。2.1）大鼠肝微粒体中醋磺己脲还原酶活性存在明显的品系和性别差异。然而，有没有品系或性别相关的差异乙酰己脲还原酶活性在大鼠肝胞液。2)镉处理间接降低雄激素调节的雄鼠肾微粒体中醋己脲还原酶活性。另一方面，镉处理对雄性大鼠肾脏胞液中的乙酰己脲还原酶活性没有显着影响。3.对雄性大鼠肝微粒体乙酰己脲还原酶活性频率分布的简单孟德尔遗传分析表明，乙酰己脲还原酶的表型受常染色体共显性遗传方式的调控。雌性大鼠，不像雄性大鼠，没有表现出微粒体酶活性的父母，第一子和第二子代。根据这些结果，我们认为微粒体酶活性的遗传是性别限制的，进一步的研究正在进行中，以阐明雄性大鼠肝微粒体乙酰己脲还原酶活性遗传缺陷的机制。

项目成果

Y.Imamura: "Metyrapone reductase purified partially from liver microsomes of male rats:The enzyme differs from acetohexamide reductase" Res.Commun.Mol.Pathol.Pharmacol.95・2. 219-226 (1997)

Y.Imamura：“从雄性大鼠的肝微粒体中部分纯化的甲吡酮还原酶：该酶与乙酰己酰胺还原酶不同”Res.Commun.Mol.Pathol.Pharmacol.95·2(1997)。

Y.Imamura: "Characterization of acetohexamide reductase purified from rabbit liver,kidney,and heart : Structural requirements for substrates and inhibitors" J.Biochem.121・4. (1997)

Y.Imamura：“从兔肝、肾和心脏中纯化的乙酰己酰胺还原酶的表征：底物和抑制剂的结构要求”J.Biochem.121·4（1997）。

Y.lmamura: "Acetohexamide reductase activities in liver microsomes and cytosol of cisplatintreated male rats : Cisplatin indirectly modulates the microsomal enzyme activity" Res.Commun.Mol.Pathol.Pharmacol.94. 203-210 (1996)

Y.lmamura：“顺铂治疗的雄性大鼠的肝微粒体和细胞质中的乙酰己酰胺还原酶活性：顺铂间接调节微粒体酶活性”Res.Commun.Mol.Pathol.Pharmacol.94。

Y.lmamura: "Individual variation of acetohexamide reductase activities in liver microsomes and cytosol of rats" Biol.Pharm.Bull.20. 924-926 (1997)

Y.lmamura：“大鼠肝微粒体和细胞质中乙酰己酰胺还原酶活性的个体差异”Biol.Pharm.Bull.20。

Y.Imamura: "Metyrapone reductase purified partially from liver microsomes of male rats : The enzyme differs from acetohexamide reductase" Res.Commun.Mol.Pathol.Pharmacol.96. 219-226 (1997)

Y.Imamura：“从雄性大鼠的肝微粒体中部分纯化的甲吡酮还原酶：该酶与乙酰己酰胺还原酶不同”Res.Commun.Mol.Pathol.Pharmacol.96。