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

对碳酸还原酶作为药物代谢酶的分子多样性和遗传缺陷的机制进行了研究。主要研究结果如下：1.以甲孕酮为底物，从雄性大鼠肝微粒体中部分纯化了一种酶。部分纯化的甲孕酮还原酶不具有还原乙酰六亚胺的能力。这些结果表明，甲草酮和乙酰六亚胺的酮还原反应可以被不同的乙酰还原酶所催化。2.1)不同品系和性别的大鼠肝微粒体乙酰六亚胺还原酶活性存在显著差异。然而，大鼠肝脏胞浆中的乙酰六亚胺还原酶活性没有品系或性别差异。2)镉处理可间接降低雄性大鼠肾微粒体中受雄激素调节的乙酰六亚胺还原酶活性。而镉处理对雄性大鼠肾细胞质乙酰六亚胺还原酶活性无明显影响。1)和2)中描述的结果表明，大鼠肝脏和肾脏中存在多种羰基还原酶。3.对雄性大鼠肝微粒体中乙酰六亚胺还原酶活性的频率分布进行的简单孟德尔遗传分析提供了证据，证明该表型受常染色体共显性方式的遗传调控。与雄性大鼠不同，雌性大鼠在亲代、子代一代和子代二代均不表现出微粒体酶活性。这些结果表明，雄性大鼠肝微粒体乙酰六亚胺还原酶活性的遗传受性别限制。进一步的研究正在阐明雄性大鼠肝微粒体乙酰己胺还原酶活性遗传缺陷的机制。

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.