Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation.
Peroxidative damages are thought to be a component of doxorubicin-induced cardiac toxicity. Administration of certain thiols, such as N-acetylcysteine, are reported to be protective against the cardiac toxicity and mortality associated with chronic doxorubicin administration. We have investigated the possibility that N-acetylcysteine exerts its protective effect by inhibiting doxorubicin-induced lipid peroxidation in a process mediated by a heat-labile cytosolic factor. Dialyzed rat liver cytosol plus N-acetylcysteine significantly inhibited doxorubicin-induced lipid peroxidation in a microsomal system whereas neither cytosol nor N-acetylcysteine alone does so. Concomitantly, it was observed that N-acetylcysteine is rapidly consumed in a system containing cytosol, microsomes, and doxorubicin. The inhibition of lipid peroxidation by the cytosol and accompanying N-acetylcysteine oxidation is heat labile. Rat heart cytosol showed a similar N-acetylcysteine-dependent inhibition of doxorubicin-induced lipid peroxidation, but heart cytosol was less potent than hepatic cytosol on the basis of protein content. The antioxidant property of heart cytosol as well as its capacity to oxidize N-acetylcysteine was inhibited by prior treatment of the cytosol with iodoacetic acid. This suggested that the factor possessed essential sulfhydryl groups. These results suggest that hepatic and cardiac cytosols contain heat-labile components capable of utilizing N-acetylcysteine as a substrate to suppress the doxorubicin-induced peroxidative damage to microsomes induced by doxorubicin. These components may play a role in the protective effects of N-acetylcysteine against doxorubicin-induced cardiac toxicity and mortality.
Powell
S R
SR
Molecular Toxicology, Oklahoma Medical Research Foundation, Oklahoma City 73104.
McCay
P B
PB
D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects*; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008566:Membranes / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D007461:Iodoacetates; D008054:Lipid Peroxides; D013438:Sulfhydryl Compounds; D009249:NADP; D004317:Doxorubicin; D019807:Iodoacetic Acid; D000111:Acetylcysteine