Shimojo N, Ishizaki T, Imaoka S, Funae Y, Fujii S, Okuda K
Department of Laboratory Medicine, Osaka City University Medical School, Japan.
Biochem Pharmacol. 1993 Aug 17;46(4):621-7. doi: 10.1016/0006-2952(93)90547-a.
Hepatic microsomal cytochrome P450s, which are involved in the metabolism of drugs, hormones, prostaglandins and fatty acids, change when animals develop diabetes. We studied changes in cytochrome P450 isozymes in both hepatic and renal microsomes of rats with diabetes caused by streptozocin, and compared the results with changes in catalytic activities in the microsomes. In hepatic microsomes of diabetic rats, the amount of cytochrome P450 2E1, an acetone-inducible isozyme, was two and a half times that of control rats, and that of P450 4A2, a major renal isozyme, was three times that in the controls. The amounts of cytochrome P450s 2A1, 2C6, 2C7, 3A2 and 4A3 increased in hepatic microsomes of diabetic rats, and P450 2C11 decreased. Treatment with insulin restored these to the levels in the controls. The catalytic activities of aniline hydroxylation, 7-ethoxycoumarin O-dealkylation, testosterone 2 beta, 6 beta, 7 alpha, and 16 beta-hydroxylation, and omega-, (omega-1)-hydroxylation of lauric acid were high in the hepatic microsomes of diabetic rats, and testosterone 2 alpha and 16 alpha-hydroxylation activities were low. In renal microsomes of diabetic rats, cytochrome P450s 2E1, 4A2 and K-4 were induced, and omega- and (omega-1)-hydroxylation activities were high. These changes were reversed by insulin treatment. The induction and suppression of cytochrome P450 isozymes in diabetic rats were consistent with the changes in the catalytic activities. In both hepatic and renal microsomes, P450s 2E1 and 4A2 were induced, altered metabolism of ketones and fatty acids in diabetes may contribute to these changes.
参与药物、激素、前列腺素和脂肪酸代谢的肝微粒体细胞色素P450在动物患糖尿病时会发生变化。我们研究了链脲佐菌素诱导的糖尿病大鼠肝脏和肾脏微粒体细胞色素P450同工酶的变化，并将结果与微粒体催化活性的变化进行了比较。在糖尿病大鼠的肝脏微粒体中，丙酮诱导型同工酶细胞色素P450 2E1的含量是对照大鼠的2.5倍，主要的肾脏同工酶P450 4A2的含量是对照大鼠的3倍。糖尿病大鼠肝脏微粒体中细胞色素P450s 2A1、2C6、2C7、3A2和4A3的含量增加，而P450 2C11减少。胰岛素治疗可使这些指标恢复到对照水平。糖尿病大鼠肝脏微粒体中苯胺羟化、7-乙氧基香豆素O-脱烷基、睾酮2β、6β、7α和16β羟化以及月桂酸的ω-、（ω-1）-羟化的催化活性较高，而睾酮2α和16α羟化活性较低。在糖尿病大鼠的肾脏微粒体中，细胞色素P450s 2E1、4A2和K-4被诱导，ω-和（ω-1）-羟化活性较高。胰岛素治疗可逆转这些变化。糖尿病大鼠细胞色素P450同工酶的诱导和抑制与催化活性的变化一致。在肝脏和肾脏微粒体中，P450s 2E1和4A2均被诱导，糖尿病中酮类和脂肪酸代谢的改变可能导致了这些变化。
