Structural requirements for cytoprotective agents in galactosamine-induced hepatic necrosis.
A variety of compounds were tested for their ability to inhibit the development of galactosamine-induced hepatic necrosis when administered 12 hr after the toxicant. Hepatic necrosis in male Sprague-Dawley rats was quantified by histopathologic examination 24 hr after a hepatotoxic dose of D(+)-galactosamine HCl (400 mg/kg, ip). Compounds found to have antinecrotic activity were not able to eliminate the accumulation of calcium associated with galactosamine-induced hepatic necrosis. Potent calcium chelators (EDTA and EGTA), compounds with aminoethanethiol-chelating structures (cysteamine and penicillamine), compounds that may be metabolized to aminoethanethiol structures in vivo (N-acetylcysteine, 2-aminoethylisothiourea, and cystamine), and a compound known to alter subcellular calcium sequestration (taurine) all inhibited galactosamine-induced hepatic necrosis. Compounds without antinecrotic effects (S-methylcysteamine, thioproline, dimercaptopropanesulfonic acid, and dimercaptosuccinic acid) do not possess structural or functional characteristics of the antinecrotic agents. It is suggested that chelation of free intercellular calcium or enhanced subcellular sequestration of calcium could explain the reduction of cytotoxic consequences of hepatic calcium accumulation observed in this model.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D003538:Cystamine / Q000494:pharmacology; D003543:Cysteamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005688:Galactosamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D003543:Cysteamine; D005688:Galactosamine; D003538:Cystamine; D002118:Calcium