Although it has long been known that epidermal melanocytes produce and excrete a number of melanin-related metabolites, including 5.6-dihydroxyindole (DHI), 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and 5-S-cysteinyldopa (CD), the possible functional significance of these compounds has been so far largely overlooked. We report now evidence that DHI, DHICA and CD exert potent inhibitory effects in different in vitro models of lipid peroxidation. The compounds, at 100 microM concentration, substantially decreased malondialdehyde (MDA) formation by lipid peroxidation in rat brain cortex homogenates. At 1.2 microM concentration, DHI proved as effective as alpha-tocopherol (alpha-T), one of the most potent endogenous antioxidants, in suppressing azo-induced peroxidation of linoleic acid in phosphate buffer (pH 7.4), containing 0.10 M SDS, whereas CD and DHICA at the same concentration were less active. DHI, CD and DHICA (all in the range 25 microM-0.5 mM) were also found to inhibit Fe (II)/EDTA-induced oxidation of 0.5 mM arachidonic acid at pH 7.4, as well as MDA formation by iron-promoted degradation of 0.5 mM 15-hydroperoxy-5,8,11, 13-eicosatetraenoic acid (15-HPETE). In both cases the inhibitory effects were much greater than those of ascorbic acid and glutathione. These results point to melanin precursors as a novel class of biological antioxidants which may contribute to defense mechanisms against oxidative injury in human skin.