The effect of dehydroepiandrosterone (DHEA), a free radical- and lipid peroxide-inducing agent, and of vitamin E (alpha-tocopherol), a free radical chain terminator, on protein carbonyl group formation was investigated in rat liver microsomes. Administration of alpha-tocopherol at 25-50 mg/kg diet for seven days resulted in high Fe(2+)-NADPH-ADP-dependent production of protein carbonyl groups in liver microsomal protein isolated from otherwise untreated rats. However, alpha-tocopherol administered at > 100 mg/kg diet caused a decrease in the production of protein carbonyl groups. In animals simultaneously receiving alpha-tocopherol at 50 mg/kg diet and DHEA at 500 mg/kg diet, no additional stimulatory effect of the steroid on microsomal protein carbonyl group production was observed. Protein carbonyl group production was significantly enhanced by DHEA in rats given a diet containing 400 mg alpha-tocopherol/kg diet. Microsomes isolated from rats fed 1,000 mg alpha-tocopherol/kg diet with DHEA (500 mg/kg diet) and without DHEA produced small but similar amounts of protein carbonyl groups. These results provide evidence that vitamin E is an important protective agent against DHEA-mediated oxidative damage of intracellular components, including proteins.