Lysosomal Leakage and Lack of Adaptation of Hepatoprotective Enzyme Contribute to Enhanced Susceptibility to Ethanol‐Induced Liver Injury in Female Rats

Background:  Women exhibit greater liver damage than men after chronic alcohol consumption. Similar findings are reported in animal models. Here, we determined whether differential liver injury occurred in male and female rats after feeding these animals liquid diets containing either ethanol or isocaloric dextrose with fish oil as the sole source of lipid. Methods:  Control and ethanol liquid diets containing fish oil were pair‐fed to male and female rats for 8 weeks. Liver damage was evaluated by triglyceride accumulation, lipid peroxide formation, serum transaminases, histological evaluation, and the activities of selected lysosomal and hepatoprotective enzymes. Results:  Fatty liver was detected after ethanol feeding in both genders, but in female rats, triglyceride levels were 60% higher, lipid peroxides were 2‐fold higher, and inflammatory cells were more evident than in males. A 2‐fold elevation of cathepsin B in hepatic cytosol fractions, indicating lysosomal leakage, was detected in ethanol‐fed female rats but no such elevation was observed in males. The basal activity of the hepatoprotective enzyme, betaine‐homocysteine methyltransferase was 4‐fold higher in livers of control male rats than females, and the enzyme activity was further elevated in ethanol‐fed male rats but not in females. Conclusions:  Thus, female rats given ethanol in a diet containing fish oil exhibited more severe liver damage than males. We propose that this difference results, in part, from a greater tendency by females to accumulate hepatic fat, thereby enhancing the potential for oxidative stress, which in turn leads to hepatic inflammation. In addition, our findings indicate that female rats have a higher susceptibility to liver damage because of a reduced capacity for hepatoprotection.