UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

Abstract

Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross of Xiphophorus fish. We used electron paramagnetic resonance to quantitatively detect the UV induction of reactive melanin radicals in situ in the melanin-containing cells in the skin of this model and derived the action spectrum for melanin-photosensitized oxidant production (⌽ ox). This action spectrum was identical to that for melanoma induction (⌽ mel). These results confirm the hypothesis that melanin-photosensitized radical production is the major causative step of melanoma in this model and demonstrate that the wavelengths and mechanisms of melanoma causation in different models are dependent on the presence of melanin. This approach should be applicable to humans, thus providing an accurate surrogate for ⌽ mel for prevention studies.action spectrum ͉ free radical C utaneous malignant melanoma incidence continues to increase (1), yet prevention strategies are hindered by a lack of knowledge of which wavelengths of sunlight cause melanoma, and the mechanisms by which these different wavelengths cause melanoma are not understood. Although nonmelanoma skin cancers are predominantly caused by UVB wavelengths, melanoma causation has efficiently been observed by wavelengths longer than UVB, such as UVA, with this observation supported by both experimental animal (2-4) and human epidemiological evidence (5-7). However, the role of UVA in melanoma causation still remains controversial (8, 9). Similarly, there is controversy over the mechanisms by which these different wavelengths act. The prevailing view is that UVA leads to DNA photooxidation, with melanin thought to be the important photosensitizer when present, whereas UVB leads to pyrimidine dimer formation through direct absorption by DNA (6, 10). The relative importance of UVB and UVA in these processes is, however, currently under scrutiny, because some have found that UVA appears able to produce pyrimidine dimers in cultured cells (11,12), whereas melanin can act as an efficient UVB sensitizer in vivo (13), and so these questions need further investigation.The question of which wavelengths cause a biological effect, in this case melanoma, is best evaluated through measuring the wavelength dependence of that effect to generate its action spectrum (14). Although melanoma has been observed in many species (15), there is only one model in which the action spectrum of melanoma causation has been determined, namely select interspecies crosses of Xiphophorus fish (4, 16). Despite the phylogenetic distance between Xiphophorus and humans, and the differences in skin structure...

Ultraviolet A does not induce melanomas in a Xiphophorus hybrid fish model

“…Given our data, the action spectrum for melanoma does not correlate with the action spectrum for melanin radicals in Xiphophorus adult and neonatal fish (18). Hence, UVA-induced melanin radicals do not appear to be involved in melanomagenesis in this animal model.…”

“…Hence, there is no significant difference in the amount of melanin radicals produced by UVA and UVB at comparable doses. Given the quantitative similarity in the melanin radicals induced by UVA and UVB (18) and the relative inefficiency of ROS induction by UVB (23,24), we suggest that free radicals are not significantly involved in UVB-induced melanoma in the fish model. If ROS do not induce melanomas, it follows that the direct DNA damage associated with UVB plays a major role in the initiation of melanomas.…”

Ultraviolet Light as a Modulator of Melanoma Development

“…Thus the fish experiments are carried out in the dark, and activation (by light) of the photolyase reduces melanoma incidence to background levels. Recently Timmins and colleagues used electron paramagnetic resonance assays to show that the action spectrum for melanoma and melanin radical production overlap (Wood et al, 2006), further evidence for melanin radical causation. However the notion that UVA is more effective than UVB in inducing melanoma in fish has been questioned by Mitchell et al, (2010), after similar experiments using apparently the same strain of fish.…”

“…One would expect that if melanin sensitization were an important mechanism, we would not see the huge increase in melanoma risk for patients with XP, unless they also lacked a defence against the melanin radicals.However there remains an anomaly that Africans with albinism (i.e. no melanin, or low levels), who practice poor sun protection, have been consistently shown to only very rarely develop melanoma (reviewed in Wood et al, 2006). In 164 such patients in Tanzania actinic keratoses were found in 100%, and SCC in 34%, of albino individuals over 30 years old, but no melanomas were found (Lookingbill et al, 1995).…”

Evolution of a Doxycycline-Induced Phototoxic Rash With an Unusual Distribution

“…2 Although melanin absorbs UV radiation and acts as an antioxidant, it may oxidize at higher doses which leads to additional cell damage. 3 The clinical presentation of doxycycline induced phototoxicity may vary from a sunburn-like sensation to diffuse erythematous plaques on sun-exposed areas. 4,5 The rash generally resolves within 10-14 days after discontinuation of the drug.…”