Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

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Abstract

To assess possible links between ethanol-induced oxidant stress, expression of hepatic cytochrome P450 (CYP) enzymes, and sex steroid status, we used immunohistochemical methods to compare the generation of protein adducts of acetaldehyde (AA), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) with the amounts of CYP2E1, CYP2A, and CYP3A in the livers of castrated and noncastrated male micropigs fed ethanol for 12 months. In castrated micropigs, ethanol feeding resulted in accumulation of fat, hepatocellular necrosis, inflammation, and centrilobular fibrosis, whereas only minimal histopathology was observed in their noncastrated counterparts. CYP2A and CYP3A were more prominent in the castrated animals than in the noncastrated micropigs. Ethanol feeding increased the hepatic content of all CYP forms. The most significant increases occurred in CYP2E1 and CYP3A in the noncastrated animals and in CYP2E1 and CYP2A in the castrated animals. Ethanol-fed castrated animals also showed the greatest abundance of perivenular adducts of AA, MDA, and HNE. In the noncastrated ethanol-fed micropigs a low expression of each CYP form was associated with scant evidence of aldehyde-protein adducts. Significant correlations emerged between the levels of different CYP forms, protein adducts, and plasma levels of sex steroids. The present findings indicate that the generation of protein-aldehyde adducts is associated with the induction of several cytochrome enzymes in a sex steroid-dependent manner. It appears that the premature, juvenile, metabolic phenotype, as induced by castration, favors liver damage. The present findings should be implicated in studies on the gender differences on the adverse effects of ethanol in the liver.

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