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

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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.