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

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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.