The plant-derived phenolic compounds gossypol, quercetin and myricetin are powerful inhibitors of iron-induced lipid peroxidation in rat liver microsomes, under all five experimental conditions tested and at low micromolar concentrations (IC50 less than or equal to 1.5 microM). However, they greatly accelerate the generation of hydroxyl radicals (.OH) from H2O2 in the presence of Fe3+-EDTA at pH 7.4, as measured by the deoxyribose assay. At 100 microM, the three phenolic compounds enhanced .OH formation up to eight-fold. The hydroxyl radical generation was inhibited by catalase and superoxide dismutase, suggesting a mechanism in which the phenols oxidize to produce superoxide radical, which then assists .OH generation from H2O2 in the presence of Fe3+-EDTA. At concentrations up to 75 microM, quercetin and myricetin also accelerate bleomycin-dependent DNA damage in the presence of Fe3+, possibly by reducing the Fe3+-bleomycin-DNA complex to the Fe2+ form. Hence these naturally-occurring substances can have pro-oxidant effects under some reaction conditions and cannot be classified simplistically as "antioxidants".