Effect of BCNU pretreatment on diquat-induced oxidant stress and hepatotoxicity.
Diquat administration produces hepatic necrosis in male Fischer-344 rats, and minimally in male Sprague-Dawley rats, with massive oxidant stress observable in both strains as evidenced by increased biliary efflux of glutathione disulfide (GSSG). Pretreatment of both strains of rats with 80 mg/kg of 1,3-bis(2-chloroethyl)-N-nitrosourea (BCNU) inhibited hepatic glutathione reductase by 75 percent and increased dramatically the biliary efflux of GSSG produced by administration of diquat. BCNU pretreatment markedly potentiated diquat hepatotoxicity in the Fischer rats and modestly in Sprague-Dawley rats. BCNU-pretreated Fischer rats did not show an enhanced depletion of nonprotein sulfhydryls in response to diquat, in spite of the dramatic potentiation of the hepatic necrosis produced, nor were protein thiols depleted. The effects of BCNU on diquat hepatotoxicity in the Fischer rat are consistent with a critical role for reactive oxygen species in the pathogenesis of the observed hepatic necrosis and for the protective role of the glutathione peroxidase/reductase system. The data suggest that shifts in thiol-disulfide equilibria are not responsible for the cell death produced by oxidant stress in vivo, but are consistent with a role for lipid peroxidation in the pathogenesis of the lesion.
D000818:Animals; D002330:Carmustine / Q000633:toxicity*; D004178:Diquat / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D011726:Pyridinium Compounds; D004178:Diquat; D005980:Glutathione Reductase; D005978:Glutathione; D002330:Carmustine; D019803:Glutathione Disulfide