Estradiol-induced effects on glutathione metabolism in rat hepatocytes

Glutathione plays an important role in the intracellular protection against oxidative stress and damage in the liver. It is generally assumed that the toxic potential of estrogens is linked to reactive metabolites generated during their enzymatic oxidation in hepatic microsomes. In the present study, the effects of pharmacological doses of estradiol on glutathione metabolism using isolated rat hepatocytes are described. Estradiol (0.1-1.5 mM) produced a dose-dependent depletion of cellular reduced glutathione (GSH), whereas it did not alter the glutathione disulfide (GSSG) excretion into the medium. The viability of cells exposed to the estrogen did not change even when conditions of exacerbated toxicity (addition of either 1 mM diethylmaleimide or 30 microM dicoumarol) were used. In addition, estradiol was shown to exert protective effects against the spontaneous lipid peroxidation in liver cells. In rat liver microsomes, estradiol (5-50 microM) significantly interacted with GSH only when an NADPH-regenerating system was incorporated into the medium.