Establishment of model animals for polymorphic drug metabolism associated with CYP2D

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The human genetic polymorphism associated with CYP2D,typically manifested in the marked inter-individual differences in debrisoquin metabolism, is of chinical importance. To study the adverse effect of drugs metabolized by CYP2D in poor metabolizer individuals, the development of the appropriate experimental animals is needed. We found that a species of wild rodents, Clethrionomys rufocanus, widely inhabiting in Hokkaido exhibits polymorphism similar to that observed in humans. We kept them in the laboratory and characterized their drug metabolizing enzyme activities. The activities of their drug metabolizing enzymes are similar to those of male rats. We found no sex difference in drug metabolism that are observed in rats. Their CYP isozymes were detectable by anti-rat CYP antibodies. Their responses to the treatment with archetypal inducers of CYP in rats are similar to those of rats. from these results, we could conclude that these rodents can be useful experimental animals for the study of CYP2D genetic polymorphism. DA rats also show very low CYP2D dependent monooxygenase activities as compared with other strains of rats. We found that the reduced expression of mRNA and protein of CYP2D2 isozyme is responsible for the reduced monooxygenase activities in this strain of rats. We also cloned cDNAs of novel CYP2D isozymes from dogs (CYP2D15) and rabbits (CYP2D23 and 2D24) and expressed and characterized these new isozymes.