CHOLESTERYL HEMISUCCINATE TREATMENT PROTECTS RODENTS FROM THE TOXIC EFFECTS OF ACETAMINOPHEN, ADRIAMYCIN, CARBON-TETRACHLORIDE, CHLOROFORM AND GALACTOSAMINE

In addition to its use as a stabilizer/rigidifier of membranes, choles teryl hemisuccinate, tris salt (CS) administration has also been shown to protect rats from the hepatotoxic effects of carbon tetrachloride (CCl4). To further our understanding of the mechanism of CS cytoprotec tion, we examined in rats and mice the protective abilities of CS and the non-hydrolyzable ether form of CS, gamma-cholesteryloxybutyric aci d, tris salt (CSE) against acetaminophen-, adriamycin-, carbon tetrach loride-, chloroform- and galactosamine-induced toxicity. The results o f these studies demonstrated that CS-mediated protection is not select ive for a particular species, organ system or toxic chemical. A 24-h p retreatment of both rats and mice with a single dose of CS (100mg/kg, i.p.), resulted in significant protection against the hepatotoxic effe cts of CCl4, CHCl3, acetaminophen and galactosamine and against the le thal (and presumably cardiotoxic) effect of adriamycin administration. Maximal CS-mediated protection was observed in experimental animals p retreated 24 h prior to the toxic insult. These data suggest that CS i ntervenes in a critical cellular event that is an important common pat hway to toxic cell death. The mechanism of CS protection does not appe ar to be dependent on the inhibition of chemical bioactivation to a to xic reactive intermediate (in light of the protection observed against galactosamine hepatotoxicity). However, based on the data presented, we can not exclude the possibility that CS administration inhibits che mical bioactivation. Our findings do suggest that CS-mediated protecti on is dependent on the action of the intact anionic CS molecule (non-h ydrolyzable CSE was as protective as CS), whose mechanism has yet to b e defined. (C) 1997 Elsevier Science Ireland Ltd.