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1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F-344) rats but not in Sprague-Dawley (SD) rats. While Kupffer cell-dependent oxidative stress plays a role in the progression of 1,2-DCB-mediated liver injury, we hypothesize that initiation of liver injury is due to oxidative events within the hepatocyte. This study compared hepatocellular oxidative stress marked by glutathione disulfide (GSSG) and glutathione (GSH) production in either bile, liver, or isolated hepatocytes of F-344 and SD rats following 1,2-DCB administration. Hepatic GSH concentrations were depleted at a greater rate in F-344 than in SD rats within 12 h of 1,2-DCB administration (3.6 mmol/kg ip). In bile, GSSG concentrations were threefold greater 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 cellular GSSG concentrations following 1 h of 1,2-DCB (3.55 nmol) exposure, while 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% reduction in GSH. Furthermore, parameters of lipid peroxidation were increased in F-344 rats and not in SD rats. Collectively, these data suggest that hepatocellular oxidative stress is dependent upon bioactivation and the enhanced oxidative stress in the F-344 rat may explain its susceptibility to 1,2-DCB compared to the SD rat., (Copyright 2000 Academic Press.)

The hepatotoxicity of 1,2-dichlorobenzene (1,2-DCB) was studied in Fischer-344 (F344) rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e., PEG-SOD) to scavenge superoxide anions. In rats not pretreated with phenobarbital (PB), administration of either MP or PEG-SOD dramatically reduced the severity of 1,2-DCB-induced liver injury. Both agents reduced the elevations in plasma ALT activities by 80%. PEG-SOD conferred protection when administered 2 hr before or 2 hr after 1,2-DCB. Light microscopic examination of H & E-stained liver sections confirmed that the reductions in plasma ALT activities reflected protection from hepatocellular injury. Interestingly, MP did not protect against 1,2-DCB-induced hepatotoxicity in PB-pretreated rats. The degree of inhibition of 1,2-DCB hepatotoxicity by PEG-SOD in PB-pretreated animals was also less than that in normal rats and was not significantly different. The lack of a significant inhibition of the PB-potentiated hepatotoxicity by both PEG-SOD and MP suggests that reactive oxygen species released from a nonparenchymal source were not as crucial to the 1,2-DCB hepatotoxicity in the PB-pretreated rats as in the normal rats. Our results using both MP and PEG-SOD support the hypothesis that reactive oxygen species released from Kupffer cells play a major role in the progression of 1,2-DCB hepatotoxicity in the F344 rat.

The acute hepatotoxicity of the three isomers of dichlorobenzene (DCB) was evaluated in male Fischer-344 (F344) rats at various times following ip administration. Plasma alanine aminotransferase (ALT) activity, measured in F344 rats 24 hr postexposure, was dramatically elevated following doses of 1.8-5.4 mmol/kg of o-DCB. Conversely, equimolar doses of p-DCB produced no such toxicity, while m-DCB produced intermediate hepatic injury at or above doses of 2.7 mmol/kg. Histopathological changes in livers from treated animals qualitatively reflected elevations in 24-hr plasma ALT activity (time to maximal elevation). Phenobarbital pretreatment potentiated the acute hepatotoxicity of o- and m-DCB, but did not affect the toxicity of p-DCB. Likewise, SKF-525A pretreatment inhibited the hepatotoxicity of o-DCB. Equimolar doses of o- and m-DCB produced approximately equivalent depletion of intrahepatic glutathione, while p-DCB had no effect on hepatic GSH. Furthermore, prior depletion of hepatic glutathione by pretreatment with phorone markedly potentiated the hepatotoxicity of o- and m-DCB, while increasing the toxicity of p-DCB to a far lesser degree. The differential hepatotoxicity of the o- and m-DCB does not appear to be explained adequately by differences in their hepatic distribution or in vivo covalent binding to hepatic proteins. Interestingly, male Sprague-Dawley (SD) rats are relatively refractive to the acute hepatotoxicity of o-DCB following ip administration of 1.8 and 5.4 mmol/kg. The combination of these dramatic differences (structure-activity and animal strains) should be useful in elucidating key events involved in the hepatotoxicity caused by these compounds.