Correlation between the spontaneous hepatitis and hepatoma and the disorder of methyl group metabolism in LEC rats

在服用胆碱缺乏饮食的肝炎和肝癌易感大鼠(LEC大鼠)中，观察到肝脏药物代谢酶的显著变化。饲喂胆碱缺乏饲料的LEC和LEA大鼠肝微粒体中的细胞色素P-450降低了催化戊氧基苯丙氨酸氧化的能力，而不是乙氧基苯丙氨酸。在LEC大鼠的自发肝癌变过程中，其他混合功能氧化酶活性也可能发生类似的选择性变化。LEC和LEA大鼠肝微粒体细胞色素P-450；pb&gt；含量和LEC大鼠4周和3月龄肝细胞色素P-450&lt；mc&gt；维持的组成水平有显著差异。胆碱缺乏引起两大类细胞色素P-450、P-450、PB&GT和P-450-MC&GT水平显著降低。GST-Yp显著升高，GST-Ya、Yb1、Yb2显著降低。LEC大鼠模拟LEA大鼠(LEC的对照大鼠)饲喂胆碱缺乏饲料，观察上述酶的变化。乙硫氨酸处理的LEC大鼠的酶变化也类似于喂养胆碱缺乏饮食的LEA大鼠。这些结果提示LEC大鼠在甲基代谢方面存在缺陷，包括DNA低甲基化。低甲基化可能参与了LEC大鼠肝炎和肝癌的发病过程。这种低甲基化可能会启动肝细胞自发地发展为肝炎和肝癌。

Marked alterations of hepatic drug-metabolizing enzymes were observed in hepatitis- and hepatoma-predisposed rats (LEC rats) fed a choline-deficient diet. The diet enhanced the development of hepatitis with severe jaundice.Cytochrome P-450 in hepatic microsomes from LEC and LEA rats fed a choline-deficient diet has reduced capacity to catalyze the oxidation of pentoxyresorufin rather than ethoxyresorufin. Similar selective changes in other mixed function oxidase activities may occur in the spontaneous hepatic carcinogenesis of LEC rats. The great difference in the cytochrome P-450_<PB> content of liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P-450_<MC> in the LEC rats at 4 weeks and 3 months of age had been previously shown. The choline-deficient diet caused marked decreases of the levels of two major classes of cytochrome P-450, P-450_<PB> and P-450_<MC>. GST-Yp was dramatically increased, whereas GST-Ya, Yb1, and Yb2 were decreased. LEC rats mimic LEA rats (the control rats to LEC) fed a choline-deficient diet in terms of the above enzyme alterations. The enzyme changes in LEC rats treated with ethionine are also similar to those observed in LEA rats fed a choline-deficient diet. These results suggest that LEC rats have some defects in methyl-group metabolism, including DNA hypomethylation. It is likely that hypomethylation is involved in the pathogenesis of hepatitis and hepatoma in LEC rats. Such hypomethylation may initiate the hepatocytes that spontaneously develop hepatitis and hepatoma.