Yamazoe Y, Murayama N, Shimada M, Yamauchi K, Kato R
Department of Pharmacology, School of Medicine, Keio University, Tokyo, Japan.
Arch Biochem Biophys. 1989 Feb 1;268(2):567-75. doi: 10.1016/0003-9861(89)90324-x.
The effects of pituitary and pancreatic hormones on the change in hepatic cytochrome P450s were studied in alloxan- or streptozotocin-induced male rats. In two major sex-specific forms, P450-male and P450(6 beta-1), the former was decreased in chronic (5 week) diabetes to only less than one-third of controls and the latter was also reduced in early (1 week) diabetes. In contrast, a main phenobarbital-inducible form, P450b, was enhanced 25- to 30-fold in these diabetic rats. 3-Methylcholanthrene-inducible P448H was also elevated 3-fold in alloxan-induced diabetes. These changes in hepatic contents of P450-male, P450-6 beta-1, and P450b, which are under the regulation of pituitary growth hormone, associated well with the reported results of time-dependent changes in growth hormone levels in diabetes (G.S. Tannenbaum (1981) Endocrinology 108, 76-82), suggesting that the change in growth hormone level is a factor responsible for alterations in hepatic cytochrome P450s. Normalizing effects of insulin on these forms were also studied. Treatment of diabetic rats with insulin reversed the decreased amounts of both P450-male protein and mRNA. Insulin also normalized hepatic contents of P450b, P4506 beta-1, and P448H. However, the treatment of hypophysectomized rats with insulin had no effect, and treatment of diabetic rats with growth hormone or a suppressing agent of somatostatin, cysteamine, showed trivial effects on P450-male and P450b. These results suggest that insulin does not act directly as a substitute of growth hormone, but exerts its effect indirectly through the normalization of a growth hormone-mediated process(es) in diabetic rats.
在四氧嘧啶或链脲佐菌素诱导的雄性大鼠中，研究了垂体和胰腺激素对肝细胞色素P450变化的影响。在两种主要的性别特异性形式中，即P450-雄性和P450(6β-1)，前者在慢性（5周）糖尿病中降至对照组的不到三分之一，后者在早期（1周）糖尿病中也减少。相反，一种主要的苯巴比妥诱导形式P450b在这些糖尿病大鼠中增加了25至30倍。在四氧嘧啶诱导的糖尿病中，3-甲基胆蒽诱导的P448H也升高了3倍。这些受垂体生长激素调节的P450-雄性、P450-6β-1和P450b肝含量的变化与糖尿病中生长激素水平随时间变化的报道结果密切相关（G.S. Tannenbaum（1981年）《内分泌学》108，76-82），表明生长激素水平的变化是肝细胞色素P450改变的一个因素。还研究了胰岛素对这些形式的正常化作用。用胰岛素治疗糖尿病大鼠可逆转P450-雄性蛋白和mRNA含量的降低。胰岛素还使P450b、P4506β-1和P448H的肝含量正常化。然而，用胰岛素治疗垂体切除的大鼠没有效果，用生长激素或生长抑素的抑制剂半胱胺治疗糖尿病大鼠对P450-雄性和P450b的影响很小。这些结果表明，胰岛素不是直接作为生长激素的替代品起作用，而是通过使糖尿病大鼠中生长激素介导的过程正常化来间接发挥作用。
