Inhibition of doxorubicin-induced membrane damage by thiol compounds: Toxicologic implications of a glutathione-dependent microsomal factor

The hypothesis was tested that glutathione exerts its protective actions against doxorubicin-induced oxidative stress through an enzyme-dependent mechanism. Glutathione at biological concentrations decreased doxorubicin-dependent rat hepatic microsomal lipid peroxidation, whereas N-acetylcysteine had no effect. Glutathione was utilized during this inhibition at a rate dependent on the concentration of both doxorubicin and the sulfhydryl. Increasing glutathione concentrations resulted in significant increases in utilization. N-acetylcysteine was also oxidized in the microsomal system; however, the rate of oxidation was not enhanced by doxorubicin. If bovine cardiac microsomes were substituted for the hepatic microsomes, no lipid peroxidation was detected in the presence of doxorubicin, yet significant utilization of glutathione was detected. Microsomes isolated from tocopherol-deficient rats utilized less glutathione in the presence of doxorubicin, and there was no inhibition of doxorubicin-dependent lipid peroxidation. These findings support the conclusion that glutathione inhibits hepatic microsomal lipid peroxidation initiated by the redox-cycling of doxorubicin. Inhibition of doxorubicin-dependent lipid peroxidation appears to be enzyme-mediated and to require tocopherol. A similar mechanism for protection against doxorubicin appears to be present in heart microsomal membranes.