Molecular and biochemical studies on the species differences of cytochrome P-450 related to forms expressed specifically in respective male and female rats

在先前的研究中，我们澄清了药物和毒物的作用和毒性的性别相关差异的发生可以通过存在性别特异性的细胞色素P450（p -450-雄性和p -450-雌性）肝微粒体来解释。因此，本研究的目的是研究在包括人类在内的其他动物的微粒体中，细胞色素P-450是否具有与P-450-雄性相似的性质。研究了细胞色素P-450形态的功能。在这个研究项目的过程中，我们获得了以下结果：1)所有动物的肝微粒体中均存在抗p -450雄性抗体免疫化学反应蛋白。不同动物体内睾酮羟化酶活性的变化表明，细胞色素P-450与P-450-雄性相关的功能在动物体内并不一定相同。2)在细胞色素P-450和睾酮羟化酶活性方面，仓鼠存在显著的性别差异。这些都是由生长激素调节的。3)从比格犬肝微粒体中纯化的细胞色素P-450与P-450相关的免疫化学形式显示出类似的药物氧化活性，但在类固醇羟基化方面存在差异。4)获得了与P-450-male同源序列的cDNA克隆，并在酵母中表达。综上所述，这个研究项目是与提案一起完成的，但要高得多。

In previous studies, we clarified that the occurrence of the sex-related differences in the actions and toxidities of drugs and toxicants could be accounted for by the presence of sex-specific forms of cytochrome P450(P-450-male and P-450-female) inliver microsomes of rats. Thus, the purpose of this research was to examine the possibility of whether are forms of cytochrome P-450 with properties similar to P-450-male in microsomes of other animal species including humans. The function of the forms of cytochrome P-450 was also studied.During the course of this research projects, we obtained results as follows; 1) Proteins immunochemically reactive with anti-P-450-male antibodies were present in liver microsomes of all animals examinned. The activities of hydroxylases of testosterone, varied animal species, indicating that the functions of cytochrome P-450 related to P-450-male were not necessarily identical among animals. 2)In the first evidence that hamster showed significant sex differences in the population of cytochrome P-450 as well as the activities of testosterone hydroxylases. These were regulated by groth hormone. 3)Forms of cytochrome P-450 immunochemically related to P-450-male, which were purified from liver microsomes of beagle dogs, showed drug oxidation activities in a similar fashion but differed with each other in steroid hydroxylations. 4)A cDNA clone with sequences homologous to P-450-male were obtained and expressed in yeast.In conclusion, this research project was completed along with the proposedule, but to much higher extsnts.