Glutathione plays an important role in the intracellular protection ag
ainst oxidative stress and damage in the liver. It is generally assume
d that the toxic potential of estrogens is linked to reactive metaboli
tes generated during their enzymatic oxidation in hepatic microsomes.
In the present study, the effects of pharmacological doses of estradio
l on glutathione metabolism using isolated rat hepatocytes are describ
ed. Estradiol (0.1-1.5 mM) produced a dose-dependent depletion of cell
ular reduced glutathione (GSH), whereas it did not alter the glutathio
ne disulfide (GSSG) excretion into the medium. The viability of cells
exposed to the estrogen did not change even when conditions of exacerb
ated toxicity (addition of either 1 mM diethylmaleimide or 30 muM dico
umarol) were used. In addition, estradiol was shown to exert protectiv
e effects against the spontaneous lipid peroxidation in liver cells. I
n rat liver microsomes, estradiol (5-50 muM) significantly interacted
with GSH only when an NADPH-regenerating system was incorporated into
the medium.