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

本研究旨在将过氧化体药物代谢反应应用于评价药物的药理和毒理作用。本研究取得的研究成果总结如下：1.过氧化体药物代谢反应的特点：已证实药物酰基部分的氧化链缩短完全是由过氧化体β-氧化系统完成的，这是由于与这些反应相关的酶的底物专一性。药物诱导过氧化物酶的影响因素：考察了药物诱导过氧化物酶的构效关系和物种差异，以及钙拮抗剂对酶诱导的影响。过氧化物酶活性测定的筛选方法：利用培养的大鼠肝细胞，获得与体内实验相似的药物效应。药物诱导过氧化物酶的药理学和毒理学评价：根据对氯贝特等药物作用的长期实验结果，认为由诱导过氧化物酶引起的氧化应激可能是导致肝癌发生的主要过程的假说不太可能被接受。本研究的结果表明，测定过氧化体药物的代谢活性对于评估药物的药理和毒理作用是重要的，特别是在过氧化体增殖剂的情况下。

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.