1,2-dichlorobenzene-mediated hepatocellular oxidative stress in Fischer-344 and Sprague-Dawley rats

1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 34 4 (F-344) rats but not in Sprague-Dawley (SD) rats. While Kupffer cell-depe ndent oxidative stress plays a role in the progression of I,2-DCB-mediated liver injury, we hypothesize that initiation of liver injury is due to oxid ative events within the hepatocyte. This study compared hepatocellular oxid ative stress marked by glutathione disulfide (GSSG) and glutathione(GSH) pr oduction in either bile, liver, or isolated hepatocytes of F-344 and SD rat s following 1,2-DCB administration. Hepatic GSH concentrations were deplete d at a greater rate in F-344 than in SD rats within 12 h of 1,2-DCB adminis tration (3.6 mmol/kg ip). In bile, GSSG concentrations were threefold great er in F-344 rats compared to SD rats by 9 h of 1,2-DCB treatment. Moreover, 1-aminobenzotriazole but not gadolinium chloride pretreatment blocked the rise in biliary GSSG concentrations following 1,2-DCB administration. In in vitro studies, isolated hepatocytes of F-344 rats had a 15% increase in ce llular GSSG concentrations following 1 h of 1,2-DCB (3.55 nmol) exposure, w hile GSH decreased 22% by 6.5 h compared to controls. In contrast, isolated SD hepatocytes exposed to 1,2-DCB had no increase in GSSG and only an 8% r eduction in GSH. Furthermore, parameters of lipid peroxidation were increas ed in F-344 rats and not in SD rats. Collectively, these data suggest that hepatocellular oxidative stress is dependent upon bioactivation and the enh anced oxidative stress in the F-344 rat may explain its susceptibility to 1 ,2-DCB compared to the SD rat. (C) 2000 Academic Press.