title: 5,6-Dihydroxyindoles in the fenton reaction: a model study of the role of melanin precursors in oxidative stress and hyperpigmentary processes.
abstract: Increasing evidence supports the view that diffusible melanin-related metabolites do not serve merely as pigment precursors, but may also act as modulators of the responses of the pigmentary cell melanocyte to external stimuli, especially to inflammation. In this study, the effect of melanin precursors 5, 6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) on the Fenton-induced oxidation of deoxyribose was investigated as a model of the oxidative stress processes triggered by the release of iron during inflammation. DHICA caused a powerful inhibition of the H(2)O(2)-Fe(II)/EDTA oxidation under both aerobic and anaerobic conditions, proving to be more efficient than typical hydroxyl radical (HO(*)) scavengers even at low concentrations with respect to deoxyribose. Conversely, DHI in air was a prooxidant at low indole:Fe(II) ratios, but shifted to an antioxidant at higher ratios (>6). The magnitude of the prooxidant effect increased by lowering the pH of the medium or by replacing Fe(II) with Fe(III), but was suppressed by exclusion of oxygen. Both the indoles retained their effects on the Fenton reaction in the absence of EDTA, as a result of their ability to chelate iron ions as evidenced by spectrophotometric experiments. Investigation of the reaction of DHI and DHICA with the Fenton reagent led to the conclusion that the indoles interact efficiently with HO(*), yielding indolesemiquinone species which are then converted to melanin pigments by self-coupling or disproportionation. At low DHI:iron molar ratios, the ability of semiquinones, generated by autoxidation of indoles, to recycle Fe(II) ions prevails, accounting for the observed prooxidant effect. Collectively, the results of this study provide new evidence for melanogenic 5,6-dihydroxyindoles as a novel class of biological antioxidants and point to these compounds as the key to interpreting the response of melanocytes to oxidative injuries. Moreover, the rapid formation of melanin following the exposure of 5, 6-dihydroxyindoles to the Fenton oxidation suggests new mechanisms of skin hyperpigmentation associated with inflammation.
authors.affiliation: Department of Organic and Biological Chemistry, University of Naples "Federico II", Via Mezzocannone 16, I-80134 Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Novellino
authors.forename: A
authors.initials: A
authors.lastname: Napolitano
authors.forename: G
authors.initials: G
authors.lastname: Prota
mesh_terms: D002245:Carbon Dioxide / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D003855:Deoxyribose / Q000737:chemistry; D004492:Edetic Acid / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical; D017495:Hyperpigmentation / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry*; D007501:Iron / Q000737:chemistry; D008543:Melanins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology*; D010860:Pigments, Biological / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D007211:Indoles; D008543:Melanins; D010860:Pigments, Biological; D002245:Carbon Dioxide; D017665:Hydroxyl Radical; C030692:5,6-dihydroxy-2-indolylcarboxylic acid; D003855:Deoxyribose; C002986:2-pyrrolecarboxylic acid; D011392:Proline; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D007501:Iron; C033871:5,6-dihydroxyindole