The chemistry of human red hair pigments: structural challenges and biomedical implications

Several studies in the last decade have led to a quite defined picture of the oxidation of 5-S-cysteinyldopa.3 The reaction involves the formation of an o-quinone which rapidly cyclizes to give an unstable o-quinoneimine intermediate. 4 This may undergo redox exchange with cysteinyldopa leading to a dihydrobenzothiazine intermediate, or may be converted to 2H-1,4-benzothiazine species by rearrangement with or without decarboxylation. 5 Conversion of benzothiazines to pheomelanins may involve different processes, including phenolic dimerizations,6 imine-enamine reactions and radical coupling at the 2-position to give dimers7structurally related to trichochromes found in red hair and feathers.2 Oxygenated systems related to 3-oxo-2H-1,4-benzothiazine units and benzothiazole moieties are also likely to be involved in pigment formation (Scheme 2). The ability of pheomelanins to bind metal cations was well known since the early studies accounting for the accumulation of Fe(III) in the biosynthetic site. The role of this and other metal cations in directing the course of pheomelanin formation and stabilizing labile intermediates has largely been investigated. Analysis of pheomelanin containing tissues is critical for identification of individuals at high risk for skin cancer. A number of structural markers derived from tissue degradation by alkaline H2O2 have recently been identified and exploited for pheomelanin analysis in biological samples. These include benzothiazoles and thiazoles arising from either 5SCD-derived units or 2SCD-structural components,8 whose critical contribution to the pigment properties has been disclosed by analysis of human red hair . Photoconsumption and superoxide generation of a variety of synthetic pheomelanins by epr methodologies provided evidence for a higher photoreactivity of these pigments compared to eumelanins even when irradiated by UVA and visible light. These and other aspects of the reactivity of pheomelanins may provide new clues for the understanding of their biological functions.