UVA, Pheomelanin and the Carcinogenesis of Melanoma

Abstract

Cloudman S91 mouse melanoma cells vary in constitutive and inducible melanin levels. Survival, mutation induction and DNA damage were quantitated after exposure to UVB, UVA and FS20 lamps. Assuming that the observed differences are related to melanin, induced pigment is photo-protective for survival and mutation after UVB and FS20 exposure, and is photosensitizing for survival after UVA exposure. No changes in pyrimidine dimers could be measured. DNA damage in pigmented mouse melanocytes (melan-a and melan-b) was greater than that in albino melanocytes (melan-c) after UVB and FS20, and the pigmented cells were more sensitive to killing. Pigment appears to be protective for killing by UVA in these melanocytes. Human melanocytes from different skin types vary in both melanin amount and composition (eu- and pheomelanin). Effects of pigmentation on UVB responses are unclear. In UVA, heavily pigmented cells have more DNA damage than lightly pigmented cells, but are resistant to killing. Increased pheomelanin photosensitizes DNA damage in lightly pigmented cells. Since eumelanin predominates in the mouse melanoma cells and melanocytes, they are less likely than human cells to provide a satisfactory model for human solar melanomagenesis. In order to understand the mechanism of photocarcinogenesis of melanoma, melanins in human melanocytes from different pigment types should be carefully quantitated and characterized. Mutations induced in them by solar wavelength-emitting lamps with well-characterized spectra should be measured, and mutant DNA should be sequenced to determine the nature of the solar-induced lesions. Research should focus on UVA and pheomelanin.

Has removal of excess cysteine led to the evolution of pheomelanin?

“…In humans, large amounts of pheomelanin and small amounts of eumelanin are characteristic of red hair, fair skin, freckling, and green irides [25], phenotypes that are more common at high latitudes [10]. If the removal of excess cysteine has adaptive value, this should be reflected in human pigmentation patterns.…”

“…It has also been reported that more-pheomelanic individual barn owls (Tyto alba) are particularly sensitive to physiological stress caused by corticosterone compared to less-pheomelanic birds [7], and that tawny owls Strix aluco belonging to the pheomelanic morph have lower viability during adverse environmental conditions than conspecifics belonging to the eumelanic morph [8]. In humans and mice, pheomelanin increases the photosensitization of cells to UVinduced oxidative damage [9], its content being positively related to cancer risk in humans [10]. Overall, these results indicate that pheomelanin is a limiting pigment that may have important evolutionary consequences.…”

“…In contrast, the biological benefits conferred by pheomela- As far as we know, this question has only been tangentially addressed. Indeed, pheomelanin has been considered ''an accident of nature'', its adaptive value being obscure [10]. One answer may be related to the potential of pheomelanin-based traits to signal ability to cope with oxidative stress (i.e.…”

“…Since pheomelanogenesis consumes GSH [3,13], which cannot then be used to combat oxidative stress, only individuals with a high antioxidant capacity should be able to produce large amounts of pheomelanin to color their integument under high environmental oxidative stress [15]. Pheomelanin-based color is also necessary to produce skin, coat and plumage patterns that confer camouflage or concealment, and in fact it has been suggested that the persistence of pheomelanin is mainly due to its camouflage and esthetic properties [10]. These properties may favor the evolution of pheomelanin, but certainly not all pheomelanin-based color traits act as quality signals [16], nor are they involved in concealment patterns [17].…”

18-årsgrensen for solariebruk skal håndheves

“…Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin (Valverde et al, 1995). Pheomelanin has weak UVR shielding capacity relative to eumelanin, and has been shown to amplify UVA-induced ROS reactive oxygen species) (Rouzaud et al, 2005, Wenczl et al, 1998Hill and Hill, 2000). Unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers (Curtin et al, 2005).…”