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

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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.