Application of Peroxisomal Drug Metabolism Reactions to the Evaluation of Pharmacological and Toxicological Actions of Drugs

本研究将过氧化物酶体药物代谢反应应用于药物药理和毒理作用的评价。本研究的主要结果如下：1.过氧化物酶体药物代谢反应的特点：研究表明，药物酰基部分的氧化性短链反应完全由过氧化物酶体β-氧化系统完成，这是由于与这些反应相关的酶的底物特异性.影响药物诱导过氧化物酶体酶活性的因素：考察了药物诱导过氧化物酶体酶活性的构效关系、种属差异以及钙拮抗剂的作用.过氧化物酶体酶活性测定的筛选方法：采用培养的大鼠肝细胞，获得与体内实验相似的药物作用.药物诱导过氧化物酶体酶的药理学和毒理学评价：根据对氯贝丁酯等药物的效果进行的长期实验所获得的结果，过氧化物酶体氧化酶诱导引起的氧化应激可能是导致肝癌发生的主要过程的假说是不可能接受的，本研究的结果表明，过氧化物酶体药物的测定代谢活性对于为评价药物的药理学和毒理学作用提供信息是重要的，特别是在过氧化物酶体增殖剂的情况下。

The present study has been performed to apply the reactions of peroxisomal drug metabolism to the evaluation of the pharmacological and toxicological actions of drugs. The results obtained in this study are summarized as follows.1. The characteristics of peroxisomal drug metabolism reactions: It was established that the oxidative chain- shortening of acyl moieties of drugs were done exclusively by peroxisomal beta-oxidation system, being due to the substrate specificities of enzymes related to these reactions.2. Factors affecting the induction of peroxisomal enzymes by drugs: The structure-reaction relationship and species differences as well as the effect of calcium antagonists in related to enzyme induction were examined.3. The screening methods for the determination of peroxisomal enzyme activities: Using cultured rat hepatocytes, a similar effects of drugs to those in in vivo experiments were obtained.4. The pharmacological and toxicological evaluation of the induction of peroxisomal enzymes by drugs: From the results obtained by a long-term experiment on the effects of drugs such as clofibrate, a hypothesis that the oxidative stress caused by the induction of peroxisomal oxidases may be a major process to lead the hepatocarcinogenesis was unlikely to be acceptable.The results in the present study indicate that the determination of peroxisomal drug metabolizing activities is important to provide the information for the evaluation of the pharmacological and toxicological actions of drugs, especially in the cases of peroxisomal proliferators.