INCREASED HEPATOCYTE CYP2E1 EXPRESSION IN A RAT NUTRITIONAL MODEL OF HEPATIC STEATOSIS WITH INFLAMMATION

Background & Aims: Nonalcoholic steatohepatitis is morphologically ide ntical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis, The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis th at induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E 1 is associated with production of steatohepatitis. Methods: Rats rece ived a diet devoid of methionine-choline, CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fr actions by immunoblotting; CYP2E1 activity was detected by N-demethyla tion of N,N-dimethylnitrosamine (NDMA), CYP2E1 messenger RNA was analy zed by Northern blotting and slot blot hybridization. Results: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3, C YP2E1 immunostaining was increased and had a more extensive acinar dis tribution corresponding to that of the steatosis. Microsomal CYP2E1 pr otein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. Conclusions: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis , The finding of biochemical and histological similarities between thi s nutritional model of hepatic steatosis with inflammation and alcohol ic hepatitis indicates possible clues to common pathogenetic mechanism s, The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver s pecimens.