Amelioration of carbon tetrachloride-induced hepatic necrosis by post-toxicant treatment with cystamine.
A quantitative animal model was developed to study amelioration of carbon tetrachloride-induced hepatic injury by post-toxicant administration of cystamine. Amelioration of CCl4-induced injury by post-toxicant cystamine treatment was compared to prevention of injury by cystamine pretreatment and possible mechanisms of the post-toxicant cytoprotective effect were investigated. Pretreatment of rats with cystamine dihydrochloride (300 mg/kg, p.o.) 30 min prior to CCl4 (0.25 ml/kg, i.p.) prevented CCl4-induced hepatic necrosis, plasma enzyme elevations, and hepatic calcium accumulation. When administered up to 12 h after CCl4, a single oral dose of cystamine inhibited necrosis in a dose-dependent manner, but did not reduce CCl4-induced plasma enzyme elevation or hepatic calcium accumulation. Cystamine post-treatment, therefore, does not appear to inhibit toxicant-induced influx of extracellular calcium into toxicant-damaged cells. This also suggests that the influx of extracellular calcium does not necessarily constitute an irreversible event leading to cell death. The mild hypothermia induced by post-toxicant treatment with cystamine did not delay the appearance of the lesion. Evidence for a slightly earlier regeneration of hepatic tissue was noted when cystamine was administered 12 h after CCl4. However, this effect was observed too long after exposure to the toxicant to account for the protection from necrosis observed 24 h after CCl4.
J R
JR
MacDonald
A J
AJ
Gandolfi
I G
IG
Sipes
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D003538:Cystamine / Q000008:administration & dosage / Q000627:therapeutic use*; D004247:DNA / Q000096:biosynthesis; D007035:Hypothermia / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D014316:Tritium; D004247:DNA; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D003538:Cystamine; D002118:Calcium; D013936:Thymidine