Influence of Gender on Cocaine Hepatotoxicity in CF-1 Mice

Abstract

Gender is known to play a role in the bioavailability, metabolism, and lethality of many toxic substances. This study was conducted to investigate the influence of gender on cocaine hepatotoxicity (CH) and lipopolysaccharide (LPS) potentiation of CH. Male and female CF-1 mice were orally administered 20 mg/kg body weight cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration, the mice were administered 12 x 10(6) EU LPS (or equal volume of sterile saline) intraperitoneally. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were evaluated as indices of liver injury. Blood and liver glutathione (GSH), glutathione reductase (GRx), and catalase (CAT) activities were also determined to investigate the extent of oxidative stress induced by the treatments. Serum ALT and AST concentrations were elevated in all males receiving cocaine alone or cocaine + LPS. Furthermore, blood GSH and CAT were decreased and GRx activity was elevated in these same animals. Histological analysis revealed a high degree of hepatic focal necrosis in the male cocaine group, and severe hemorrhagic necrosis in the male cocaine + LPS group. Unlike males, females showed no damage resulting from cocaine or cocaine + LPS exposure, whereas testosterone-supplemented ovariectomized females displayed histological and biochemical profiles statistically similar to males. The results demonstrate that the extent of CH or LPS-potentiated CH is influenced by gender and sex hormones, particularly testosterone.