Changes in hepatic glutathione concentrations during carbon disulfide induced hepatotoxicity in the rat.
When administered acutely to male Sprague-Dawley rats, carbon disulfide (CS2, 5 mmole/kg ip) caused centrilobular hepatic hydropic degeneration or necrosis. Pretreatment with phenobarbital was a requirement for hepatotoxicity and treatment with SKF 525-A, an inhibitor of microsomal CS2 metabolism, reduced the extent of hepatotoxicity. These results support the hypothesis that the hepatotoxicity of CS2 requires metabolism by the cytochrome P-450 containing monooxygenase system. CS2-induced hepatotoxicity was not accompanied by a decrease in hepatic glutathione, but rather, an increase of approximately 50% which occurred 16 hours after CS2 administration. This increase occurred only when CS2 was given to phenobarbital pretreated rats and was prevented by prior treatment with SKF 525-A. Hence, the delayed increase in glutathione could be related to CS2-induced hepatotoxicity. Additionally, CS2-induced hepatotoxicity was not enhanced by depletion of hepatic glutathione with diethyl maleate (DEM). Many hepatotoxins that require metabolic activation cause decreases in glutathione, and the extent of hepatic damage is increased by agents that deplete hepatic glutathione. Therefore, while CS2-induced hepatotoxicity requires metabolic activation, the effects on hepatic glutathione suggests that the mechanism of CS2-induced hepatotoxicity may be distinct from other "metabolically activated" hepatotoxins.
Chengelis
C P
CP
Department of Toxicology, G.D. Searle Research and Development, Skokie, IL 60077.
D000818:Animals; D002246:Carbon Disulfide / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005978:Glutathione / Q000032:analysis*; D008099:Liver / Q000032:analysis / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D008298:Maleates; D011725:Pyridines; C013109:metapyrone; D003577:Cytochrome P-450 Enzyme System; C014476:diethyl maleate; D005978:Glutathione; D002246:Carbon Disulfide