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 obse rved in rat liver slices incubated with diethyldithiocarbamate at conc entrations between 1 and 10 mM over a 4-h period. Histological study r evealed perivenous hepatocyte damage. To examine the involvement of Ku pffer cells in diethyldithiocarbamate-induced cytotoxicity, rats were injected intravenously with 10 mg/kg of gadolinium chloride (GdCl3) wh ich diminishes Kupffer cell function. Incubation of liver slice prepar ations from the GdCl3-treated rats with diethyldithiocarbamate showed marked inhibition of the cytotoxicity induced by diethyldithiocarbamat e. Moreover, in vitro addition of manganese-superoxide dismutase, a su peroxide anion scavenger, or dimethyl sulfoxide (DMSO), a hydroxyl rad ical scavenger, also showed potent inhibition. However, dexamethasone, an inhibitor of tumor necrosis factor, and N,N'-diphenyl-p-phenylened iamine (DPPD), an antioxidant, showed partial prevention of cytotoxici ty. Formazan deposits formed as a result of nitro blue tetrazolium red uction were found in Kupffer cells at an early stage after diethyldith iocarbamate treatment, while lipid peroxidation occurred after 3 h. Bo th pretreatment with GdCl3 in vivo and addition of DMSO in vitro preve nted the increase in lipid peroxidation within the liver slice prepara tions induced by diethyldithiocarbamate. These findings suggest that K upffer cell function may be involved in the pathogenesis of diethyldit hiocarbamate hepatotoxicity.