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Abnormal Expression of Cytochrome P-450 in LEC Rats with Metabolic Predisposition to Spontaneous Hepatitis

具有自发性肝炎代谢倾向的 LEC 大鼠细胞色素 P-450 的异常表达

基本信息

批准号：
01570157
负责人：
SUGIYAMA Toshihiro
金额：
$ 1.34万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570157/
关键词：
Spontaneous hepatitis Cytochrome P-450 DNA methylation LEC rat Choline-deficient diet チトクロ-ムPー450

项目摘要

The LEC rat is a mutant strain displaying hereditary hepatitis with severe jaundice. The age related difference in microsomal de-alkylation of pen-toxyresorufin and ethoxyresorufin was examined. The enzyme activity levels of pentoxyresorufin O-depentylase in LEC rats were decreased to 25% of the levels in control (LEA) rats. In contrast, ethoxyresorufin O-deethylase exhibited a much less marked difference between the strains. In parallel with these strain differences in enzyme activities, a decrease in phenobarbital (PB) inducible P-450 isozymes, mainly P-450b and P-450e, was observed by Western blot analysis. The level of P-450_<PB> in LEC rats was more markedly depressed than in the LEA strain. On the other hand, microsomes from uninduced LEC rat liver had more 3-methylcholanthrene (MC) inducible P-450_<MC>, mainly P-450c and P-450d, than microsomes from LEA rat liver, and these isozymes in the LEC were markedly induced by 3-methylcholanthrene treatment. The great difference in cytochrome P-450_<PB> content of the liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P-450_<MC> in the LEC rats suggest a possible role of these cytochrome isozymes in the onset of a spontaneous hepatitis and hepatoma.Cytochrome P-450 in hepatic microsomes from LEC and LEA rats fed a choline-deficient diet has reduced capacity to catalyze the oxidation of pentoxy-resorufin rather than ethoxyresorufin. The choline-deficient diet caused marked decrease of the levels of two major classes of cytochrome P-450, P-450_<PB> and P-450_<MC>. 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.

LEC大鼠是一个突变株显示遗传性肝炎与严重黄疸。检查了戊氧基试卤灵和乙氧基试卤灵微粒体脱烷基化的年龄相关差异。戊氧基试卤灵O-脱戊基酶在LEC大鼠中的酶活性水平降低至对照（莱亚）大鼠中水平的25%。相比之下，乙氧基试卤灵O-脱乙基酶在菌株之间表现出不太显著的差异。与这些菌株的酶活性的差异，苯巴比妥（PB）诱导的P-450同工酶，主要是P-450 b和P-450 e，通过蛋白质印迹分析观察到的减少。LEC大鼠P-450_1水平<PB>较莱亚系大鼠明显降低。另一方面，未诱导LEC大鼠肝微粒体中的3-甲基胆蒽（MC）诱导的P-450_<MC>（主要是P-450 c和P-450 d）比莱亚大鼠肝微粒体中的多，并且LEC中的这些同工酶被3-甲基胆蒽显著诱导。LEC<PB>和莱亚大鼠肝微粒体细胞色素P-450含量的巨大差异和LEC大鼠肝细胞色素P-450的维持组成水平<MC>表明这些细胞色素同功酶在自发性肝炎和肝癌的发病中可能起作用。胆碱缺乏引起两大类细胞色素P-450，P-450_<PB>和P-450_水平显著下降<MC>。这些结果提示LEC大鼠存在甲基代谢缺陷，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。这种低甲基化可引发肝细胞自发发展为肝炎和肝癌。