Establishment of model animals for polymorphic drug metabolism associated with CYP2D

人类与CYP2D相关的遗传多态，典型地表现为脱氧核蛋白代谢的显著个体间差异，具有重要的临床意义。为了研究代谢不良个体体内代谢药物的不良反应，需要建立合适的实验动物。我们发现北海道广泛栖息的一种野生啮齿动物--红纹夜蛾表现出与人类相似的多态。我们把它们放在实验室里，并对它们的药物代谢酶活性进行了表征。它们的药物代谢酶的活性与雄性大鼠相似。我们在大鼠身上观察到的药物代谢没有性别差异。其CYP同工酶可被抗大鼠CYP抗体检测到。大鼠对CYP原型诱导剂治疗的反应与大鼠相似。这些结果表明，这些啮齿动物可以作为研究CYP2D基因多态的有用的实验动物。与其他品系的大鼠相比，DA大鼠的细胞色素P450 2D依赖的单加氧酶活性也很低。我们发现，该品系大鼠的单加氧酶活性降低与其同工酶基因和蛋白表达的减少有关。同时，我们还克隆了犬(CYP2D15)和兔(2D24)新的细胞色素P450-2D同工酶的cDNAs，并对其进行了表达和鉴定。

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.