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Toxicological Studies on Species Difference in Metabolic Toxication of Environmental Chamicals-with a Special Focus on Cytochrome P-450

环境化学物质代谢毒性物种差异的毒理学研究——以细胞色素P-450为重点

基本信息

批准号：
04404019
负责人：
FUJITA Shoichi
金额：
$ 17.28万
依托单位：
Faculty of Veterinary Medicine, Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

Genetic, age, gender and species differences, effect of liver diseases including liver cancer, effect of foreign compounds were studied with respect to activities of drug metabolizing enzyme system. Generic defect in CYP2D1 in DA rats appeared to be due to the presence of mutation in structural gene rather than impaired transcription of this particular gene as has been reported. CYP2D1 mRNA was detected and a part of cDNA sequence was reverse-transcribed by RT-PCR from mRNA of DA rats. In rats, aging had a profound effect on drug metabolizing enzyme activities in liver microsomes. Marked decrease in monooxygenase activities in male rat liver resulted in the disappearance of sex-difference in drug metabolizing activities in rats. Hepatic tissue baring liver tumor had reduced monooxygenase activities, and even more reduction was observed in tumor tissues. Alterations of monooxygenase activities were suggestive of P450 isozyme specific alterations, and this was confirmed by Western blotting analysis. With these various factors affecting drug metabolizing enzymes in mind, species difference in drug metabolizing enzyme activities was studied using dogs, foxes, minks and bears. Dogs and foxes had higher activities and mink, the lowest. The Japanese fresh water crabs had P450 concentrations and activities corresponding to the levels of polycyclic hydrocarbons in the river.

研究了遗传、年龄、性别和物种差异、包括肝癌在内的肝病的影响以及外来化合物对药物代谢酶系统活性的影响。DA大鼠的基因缺陷可能是由于结构基因的突变，而不是像已报道的那样，该基因的转录受损。用逆转录聚合酶链式反应(RT-PCR)从DA大鼠的mRNA中检测到细胞色素P450 2D1m RNA，并反转录了部分c DNA序列。在大鼠中，衰老对肝微粒体中药物代谢酶的活性有深远的影响。雄性大鼠肝脏单加氧酶活性显著降低，导致药物代谢活性的性别差异消失。裸鼠肝组织中单加氧酶活性降低，肿瘤组织中单氧合酶活性降低更明显。单加氧酶活性的改变提示P450同工酶的特异性改变，这一点经Western blotting分析得到证实。考虑到这些影响药物代谢酶的各种因素，用狗、狐狸、水貂和熊研究了药物代谢酶活性的物种差异。狗和狐狸的活动较高，水貂的活动最低。日本淡水蟹的P450浓度和活性与河流中多环烃的水平相对应。