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

研究了遗传、年龄、性别和物种差异、肝脏疾病（包括肝癌）的影响、外源化合物对药物代谢酶系统活性的影响。DA大鼠CYP2D1的一般性缺陷似乎是由于结构基因突变的存在，而不是由于该特定基因的转录受损。检测DA大鼠的CYP2D1 mRNA， RT-PCR反转录部分cDNA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明显降低，导致大鼠药物代谢活性的性别差异消失。肝脏肿瘤组织单核加氧酶活性降低，肿瘤组织单核加氧酶活性降低幅度更大。单加氧酶活性的改变提示P450同工酶特异性改变，Western blotting分析证实了这一点。考虑到这些影响药物代谢酶的各种因素，以狗、狐狸、水貂和熊为研究对象，研究了药物代谢酶活性的物种差异。狗和狐狸的活动量较高，水貂的活动量最低。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。

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.