Sex-related difference in hepatic glutathione conjugation of hexachlorobenzene in the rat

Abstract

Hexachlorobenzene (HCB) induces hepatic porphyria and liver cancer in female rats, whereas toxicity is minimal in male rats. HCB is biotransformed to sulfur-containing metabolites originating from conjugation to glutathione (GSH). This study aimed to assess differences in GSH conjugation of HCB between male and female rats. Sprague-Dawley rats of both sexes were given (po, 10 ml/kg in corn oil) five consecutive doses of 100 mg/kg HCB [2 bid (7:30, 15:30) + 1 sid (7:30)]. This cumulative dose produced porphyria in female but not male rats after a delay period of 6 weeks. Animals were killed 0, 6, 12, 18, or 24 hr after the last dose. Hepatic GSH level showed a diurnal cycle in rats of both sexes, but it was more pronounced in males; the minimum level was observed at 12 hr,after dosing. The GSH level in HCB-treated male rats was significantly lower than control at 6, 18, and 24 hr, whereas no significant differences were observed for HCB-treated female rats. Biliary excretion of pentachlorothiophenol, a metabolite originating from GSH conjugation of HCB, was higher in male than female rats. Liver cytosolic GSH transferase activity toward 3,4-dichloronitrobenzene was significantly higher than control level in male but not female rats given HCB. GSH transferase activity toward 1,2-epoxy-3-( p-nitrophenoxy)propane in male and female rats was not increased by HCB treatment. The liver HCB concentration at 24 hr after dosing was higher in male rats than in female rats but decreased faster thereafter. These results suggest that hepatic GSH conjugation of HCB is more important in male than in female rats. This may be related to the reduced liver porphyria observed in HCB-treated male rats compared to female rats.