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

研究了碳还原酶作为药物代谢酶的分子多样性和遗传缺陷的机制。得到的结果如下：1。以甲替rapone为底物，从雄性大鼠肝微粒体中部分纯化出一种酶。部分纯化的甲基曲酮还原酶没有还原乙己胺的能力。上述结果表明，不同的羰基还原酶可催化甲曲酮和乙己胺的酮还原。2.1)大鼠肝微粒体中乙己胺还原酶活性存在明显的品系和性别差异。大鼠肝细胞质乙酰己胺还原酶活性无品系、性别差异。2)镉间接降低雄性大鼠肾微粒体中受雄激素调控的乙酰己胺还原酶活性。另一方面，Cd处理对雄性大鼠肾细胞质乙酰己胺还原酶活性无显著影响。1)和2)的结果表明大鼠肝脏和肾脏中存在多重羰基还原酶。对雄性大鼠肝微粒体乙酰己胺还原酶活性频率分布的简单孟德尔遗传分析提供了该表型受常染色体共显性遗传调节的证据。与雄性大鼠不同，雌性大鼠在亲代、第一代和第二代均未表现出微粒体酶活性。基于这些结果，我们认为微粒体酶活性的遗传是有性别限制的。雄性大鼠肝微粒体乙酰己胺还原酶活性遗传缺陷的机制有待进一步研究。

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.