Role of Kupffer cells in rat liver injury induced by diethyldithiocarbamate.
The hepatotoxicity of diethyldithiocarbamate was examined using an in vitro rat liver slice system. Concentration- and time-dependent losses of intracellular K+ and adenosine triphosphate (ATP) levels were observed in rat liver slices incubated with diethyldithiocarbamate at concentrations between 1 and 10 mM over a 4-h period. Histological study revealed perivenous hepatocyte damage. To examine the involvement of Kupffer cells in diethyldithiocarbamate-induced cytotoxicity, rats were injected intravenously with 10 mg/kg of gadolinium chloride (GdCl3) which diminishes Kupffer cell function. Incubation of liver slice preparations from the GdCl3-treated rats with diethyldithiocarbamate showed marked inhibition of the cytotoxicity induced by diethyldithiocarbamate. Moreover, in vitro addition of manganese-superoxide dismutase, a superoxide anion scavenger, or dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, also showed potent inhibition. However, dexamethasone, an inhibitor of tumor necrosis factor, and N,N'-diphenyl-p-phenylenediamine (DPPD), an antioxidant, showed partial prevention of cytotoxicity. Formazan deposits formed as a result of nitro blue tetrazolium reduction were found in Kupffer cells at an early stage after diethyldithiocarbamate treatment, while lipid peroxidation occurred after 3 h. Both pretreatment with GdCl3 in vivo and addition of DMSO in vitro prevented the increase in lipid peroxidation within the liver slice preparations induced by diethyldithiocarbamate. These findings suggest that Kupffer cell function may be involved in the pathogenesis of diethyldithiocarbamate hepatotoxicity.
Ishiyama
H
H
Department of Public Health Yamaguchi University School of Medicine, Ube, Japan.
Ogino
K
K
Hobara
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D003907:Dexamethasone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004050:Ditiocarb / Q000633:toxicity*; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D013481:Superoxides; D003907:Dexamethasone; D000255:Adenosine Triphosphate; D004050:Ditiocarb; D013482:Superoxide Dismutase; D011188:Potassium; D004121:Dimethyl Sulfoxide