The bright and dark side of red hair pigments

In recent years considerable structural, chemical, and photophysical insights into red hair pigments have yielded an unprecedented molecular basis to unravel their actual roles in the susceptibility of RHC phenotypes to photodamage and the oxidative imbalance observed in dysplastic nevi and melanocytes from light phototype donors. Overall, the new knowledge that emerges from these studies points to a new picture of red hair pigments that hinges on three key points: 1) a complex molecular structure embodying as central element isoquinoline and benzothiazole-containing structural motifs; 2) a dual photochemical behavior; and 3) a marked pro-oxidant behavior even in the absence of UV stimulation. 1)Chemical degradation of red hair and the identification of thiazolylpyridine carboxylic acid fragment (TPCA) was the tool that enabled identification in the pigment backbone of the long postulated isoquinoline units. The origin of this product was elucidated by identification of two isomeric dimers featuring a TPCA- forming molecular scaffold in the biomimetic oxidation of 5-S-cysteinyldopa in the presence of Zn2+ ions. As a noticeable remark, these model compounds were found to reproduce the main chemical properties and spectral features of intact red human hair pigments like no other low molecular weight intermediate, including the trichochromes, and may therefore be taken as “the minimal pheomelanin unit”. 2) Analysis of structural markers in hair locks following prolonged exposure to sun light showed that red hair pheomelanin consists of a degradable bulk component derived from 5-S-cysteinyldopa associated to stable units derived from 2-S-cysteinyldopa, the minor biosynthetic precursor. Photoaged red hair pigment thus consists almost exclusively of 2-S-cysteinyldopa-derived structures, a finding that may profoundly alter interpretation of red hair phototoxicity. 3) Red hair pigments can promote the aerial oxidation of dopa and cysteinyldopas in the dark to give eumelanin coatings wrapping the pheomelanin core and providing a remarkable in vitro mimic of the casing model of melanosome assembly. The new data support overall a central role of pheomelanins in sustaining a pro-oxidant state and oxidative stress in the RHC phenotype..