Establishment of model animals for polymorphic drug metabolism associated with CYP2D

与CYP2D相关的人类遗传多态性，典型地表现在异喹代谢的显著个体间差异，具有临床重要性。为了研究CYP2D代谢的药物在弱代谢个体中的不良反应，需要开发合适的实验动物。我们发现，一种野生啮齿动物，Clethrionomys rufocanus，广泛居住在北海道表现出类似于在人类中观察到的多态性。我们将它们保存在实验室中并表征它们的药物代谢酶活性。其药物代谢酶活性与雄性大鼠相似。我们发现在大鼠中观察到的药物代谢无性别差异。抗鼠IgG抗体可检测到它们的抗鼠IgG同工酶。它们对用大鼠的原型诱导剂处理的反应与大鼠的相似。这些结果表明，这些啮齿类动物可作为研究CYP2D基因多态性的实验动物。与其他品系的大鼠相比，DA大鼠还显示出非常低的CYP2D依赖性单加氧酶活性。我们发现，CYP2D2同工酶的mRNA和蛋白表达的减少是导致该品系大鼠单加氧酶活性降低的原因。我们还克隆了狗（CYP2D15）和兔（CYP2D23和2D24）的新型CYP2D同工酶的cDNA，并表达和表征了这些新的同工酶。

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.