Acetaminophen-Induced Hepatorenal Toxicity in High Fructose Diet-Fed Rats Is Sex-Dependent

Abstract

Male rats with fructose-induced hypertriglyceridemia become resistant to hepatotoxicity and more susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal male rats. To determine whether changes in APAP toxicity by fructose-treatment were sex-dependent, male and female rats were fed standard diet (non-pretreated rats) or high fructose diet (fructose-pretreated rats) for 3 weeks and then given a single ip dose of APAP at 800 mg/kg. At 24 hours after APAP dosing, they were sacrificed and examined histopathologically. Non-pretreated males showed severe hepatic lesions characterized by centrilobular hepatocyte necrosis and slight renal lesions characterized by single cell necrosis in the proximal straight tubules, while females showed no hepatic lesions and milder renal lesions than males. APAP-induced hepatotoxicity was prevented and APAP-induced nephrotoxicity was potentiated in fructose-pretreated males. In contrast, no apparent changes on APAP-induced toxicity were seen in fructose-pretreated females. Castration partially prevented such enhancement of APAP-induced nephrotoxicity in fructose-pretreated males. Furthermore, castration and estradiol treatment had greater protective effect against the enhancement of APAP-induced nephrotoxicity in fructose-pretreated males as compared with castration alone. Ovariectomy potentiated the enhancement of APAP-induced nephrotoxicity in females. These results indicate that the changes in APAP-induced hepatorenal toxicity by fructose-pretreatment are sex-dependent.