1,2-dichlorobenzene-induced lipid peroxidation in male Fischer 344 rats isKupffer cell dependent

12-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in male Fischer 344 (F344) rats and previous studies have suggested that reactive oxygen speci es may play a role in the development of hepatotoxicity. Since reactive oxy gen species can damage lipid membranes, this study was conducted to determi ne the extent of lipid peroxidation after administration of 1,2-DCB by immu nohistochemical analysis of 4-hydroxynonenal (4-HNE) protein adduct formati on in liver and conjugated diene formation in liver and serum. The contribu tion of Kupffer cells to the lipid peroxidation was also investigated. Male F344 rats were administered 1,2-DCB (3.6 mmol/kg ip in corn oil) and kille d at selected times between 3 and 48 h. Time course studies revealed the gr eatest abundance of 4-HNE protein adducts in the centrilobular regions of t he liver 24 h after 1,2-DCB administration, with much lower levels at 16 h. Adducts were present in necrotic and vacuolized centrilobular hepatocytes of 1,2-DCB treated rats but not in livers of controls. Further, conjugated dienes were significantly increased in liver and serum 16 and 24 h after 1, 2-DCB administration, peaking at 24 h. These data correlated with hepatocel lular injury, determined by serum alanine aminotransferase activity and his topathological evaluation, which was markedly elevated within 16 h and peak ed at 24 h. When rats were pretreated with gadolinium chloride (GdCl3; 10 m g/kg iv 24 h prior to 1,2-DCB), an inhibitor of Kupffer cells, hepatotoxici ty was decreased by 89 and 86%, at 16 and 24 h, respectively. Conjugated di ene concentrations were decreased to control values at these times after 1, 2-DCB administration. Moreover, no 4-HNE protein adducts were detected in l ivers of 1,2-DCB-treated rats pretreated with GdCl3. Finally, Kupffer cells isolated from 1,2-DCB-treated rats produced significantly more superoxide anion than Kupffer cells isolated from vehicle controls. These data, along with previous findings, suggest that lipid peroxidation associated with 1,2 -DCB is mediated in part by Kupffer cell-derived reactive oxygen species. ( C) 1998 Society of Toxicology.