Modulation of 1,2-dichlorobenzene hepatotoxicity in the Fischer-344 rat by a scavenger of superoxide anions and an inhibitor of Kupffer cells.
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.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
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Gunawardhana
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Mobley
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Sipes
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D016166:Free Radical Scavengers; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D010168:Palmitates / Q000378:metabolism / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology
D002722:Chlorobenzenes; D016166:Free Radical Scavengers; D010168:Palmitates; D017382:Reactive Oxygen Species; D013481:Superoxides; C004726:2-dichlorobenzene; C019012:methyl palmitate; D013482:Superoxide Dismutase; D000410:Alanine Transaminase; D010634:Phenobarbital