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

LEC大鼠自发性肝炎、肝癌与甲基代谢紊乱的相关性

基本信息

批准号：
03670140
负责人：
SUGIYAMA Toshihiro
金额：
$ 1.28万
依托单位：
Akita University (1992)Osaka University (1991)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

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.

在喂食缺乏胆碱的饮食的易患肝炎和肝癌的大鼠（LEC 大鼠）中观察到肝脏药物代谢酶的显着改变。饮食促进了伴有严重黄疸的肝炎的发生。饲喂缺乏胆碱饮食的LEC和LEA大鼠的肝微粒体中的细胞色素P-450催化戊氧基试卤灵氧化的能力比乙氧基试卤灵氧化的能力降低。其他混合功能氧化酶活性的类似选择性变化可能在 LEC 大鼠的自发性肝癌发生中发生。先前已显示LEC和LEA大鼠肝微粒体中细胞色素P-450_<PB>含量的巨大差异以及LEC大鼠在4周龄和3月龄时维持的肝细胞色素P-450_<MC>组成水平。缺乏胆碱的饮食导致两类主要细胞色素 P-450（P-450_<PB> 和 P-450_<MC>）的水平显着下降。 GST-Yp 显着增加，而 GST-Ya、Yb1 和 Yb2 减少。 LEC 大鼠在上述酶的改变方面模仿 LEA 大鼠（LEC 的对照大鼠），饲喂缺乏胆碱的饮食。用乙硫氨酸治疗的 LEC 大鼠的酶变化也与饲喂缺乏胆碱饮食的 LEA 大鼠中观察到的酶变化相似。这些结果表明LEC大鼠的甲基代谢存在一些缺陷，包括DNA低甲基化。低甲基化可能参与LEC大鼠肝炎和肝癌的发病机制。这种低甲基化可能会引发肝细胞自发发展为肝炎和肝癌。