Expression of testosterone-dependent enzyme, carbonic anhydrase III, and oxidative stress in experimental alcoholic liver disease

We studied the sequential immunohistochemical appearance of androgen-depend ent carbonic anhydrase (CA III) during the development of ethanol-induced l iver injury using liver samples from castrated and noncastrated male microp igs. In castrated micropigs, the baseline expression of CA III was either l ow or absent, while distinct positive immunoreactions were found in zone 3 hepatocytes at 5 and 12 months after the initiation of the ethanol diet. Th e CA III enzyme and protein adducts of lipid peroxidation-derived aldehydic products, malondialdehyde and 4-hydroxynonenal, appeared together in the p erivenous region, suggesting that the enzyme functions in an oxidative envi ronment. The positive staining became more abundant and widespread during t he progression of alcoholic liver disease. After 12 months, CA III was sign ificantly more abundant in both the ethanol-fed noncastrated and castrated micropigs than in the control animals (P < 0.001, P < 0.05, respectively). CA III content was strikingly high in the ethanol-fed noncastrated animals, consistent with a potential role of androgens in the regulation of ethanol -induced CA III expression. The strongly positive CA III immunoreactions in the ethanol-fed noncastrated micropigs were associated with scant evidence of aldehydic protein adducts and minimal histopathology. Thus, enhanced ex pression of CA III during ethanol consumption may also account in part for gender differences in the susceptibility for alcohol-induced liver injury.