Paradoxical effect of cobaltous chloride on carbon disulfide induced hepatotoxicity in rats.
A single acute dose of carbon disulfide (CS2, 5 mmol/kg ip) caused hepatic damage in rats pretreated with phenobarbital. Rats pretreated with phenobarbital and cobaltous chloride (CoCl2, 250 mumol/kg sc) were protected against CS2 induced hepatotoxicity. When single acute doses of CS2 and CoCl2 were given at the same time, however, rats developed a much more severe hepatic lesion than that seen following CS2 alone. Similar cotreatment of CoCl2 with bromobenzene, carbon tetrachloride or thioacetamide did not enhance the hepatotoxicity of these well-studied hepatotoxins. Additionally, other divalent metal salts (CuSO4 and ZnCl2) did not enhance CS2 hepatotoxicity. Hence, the interaction between CS2 and CoCl2 (that results in enhanced CS2 induced hepatic damage) appears to be relatively specific for these two agents. CS2 caused an approximate 50% decrease in hepatic cytochrome P-450 when given alone, but an approximate 85% decrease when given with CoCl2. This observation supports the hypothesis that the breakdown products of cytochrome P-450 heme are responsible for CS2 induced hepatotoxicity. In addition, single doses of CS2 or CoCl2 caused increases of 30 to 60% in hepatic glutathione (GSH), but additive responses were not obtained when the two agents were given at the same time. GSH synthetase and gamma-glutamyl transpeptidase activity were inconsistently changed by these treatments, and did not provide a consistent explanation for the increases in GSH. The enhanced hepatotoxicity of CS2 + CoCl2 is not due to changes in hepatic glutathione metabolism.
Chengelis
C P
CP
Department of Toxicology, G. D. Searle Research & Development, Skokie, IL 60077.
D000818:Animals; D002246:Carbon Disulfide / Q000633:toxicity*; D003035:Cobalt / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D003035:Cobalt; C018021:cobaltous chloride; D005978:Glutathione; D002246:Carbon Disulfide