Dual Role of Melanins and Melanin Precursors as Photoprotective and Phototoxic Agents: Inhibition of Ultraviolet Radiation‐induced Lipid Peroxidation

Abstract

Ultraviolet radiation (UVR) is one of the risk factors for skin cancer and the main inducer of melanin pigmentation, the major protective mechanism of mammalian skin against radiation damage. The melanin pigments, eumelanin and pheomelanin, are likely to be important in protection against UVR, but their precursors are generally considered as phototoxic. The available data suggest DNA damage as the mechanism of phototoxicity. However, the effect of melanin precursors on membrane damage through lipid peroxidation, another important and probably more relevant (from the point-of-view of the melanosomal confinement of these molecules) mechanism of phototoxicity, not known. As a model system for UVR-melanin-membrane interactions, we irradiated liposomes in the presence of eumelanin, pheomelanin and two of their major precursors, 5,6-dihydroxyindole (DHI) and 5-S-cysteinyldopa (SCD). The presence of the two melanin precursors substantially reduced the formation of lipid peroxidation products resulting from UVR exposure. The antioxidant activity of the melanin precursors was diminished under strong prooxidant conditions (presence of Fe3+). These results suggest that melanin precursors may have an important role in the protection of skin against the harmful effects of UVR including photocarcinogenesis.

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers

“…Interestingly, dermal melanocytes and melanoma lines do express voltage-dependent currents (22,23) and under conditions of increased oxidative stress some ionic currents are modified to promote cellular excitability (24)(25)(26). In the skin, reactive intermediaries such as 5,6-dihydroxyindole (DHI) (27) are formed in the pheomelanin synthesis pathway. On the other hand, 5,6-dihydroxyindole-2-carboxylic acid (DHICA), which is thought to be less reactive than DHI, is formed in the eumelanin synthesis pathway, diminishing the formation of reactive species (28).…”

Photoprotection by Total Melanin Content and Pigment Phenotype (Eumelanin, Pheomelanin) in Human Melanoma Cell Lines

“…UVA and visible light are hardly (> 334 nm) or not absorbed (> 347 nm) by DNA and provoke cell injury predominantly by indirect mechanisms with the generation of toxic products such as reactive oxygen species [20,21]. Against these indirect damaging effects by UVA and visible light the pigment phenotype seems to possess more relevance than the total melanin content possibly due to the effective role of eumelanin as a radical scavenger [22].…”

Melanocyte Pygmentation – Friend or Foe on the Route to Melanoma

“…In contrast, UVA radiation is very weakly absorbed by DNA. Most of the studied biologic effects of UVA radiation, like lipid peroxidation and membrane damage are mediated by reactive oxygen species (ROS) and they are probably the major contributors to UVAinduced cell death (Tyrell, 1994;Girotti et al, 2001;Schmitz et al, 1995). Failure to eliminate UV-damaged cells through control led apoptosis may result in disease states such as skin cancer or lead to faster aging of the skin (Brash et al, 1991).…”

“…5-SCD is photochemically unstable in the presence of UVA radiation and oxygen (Costantini et al, 1994), leading to superoxide anion production (Chedekel and Zeize, 1988). UV irradiation of pheomelanin can also lead to the formation of hydroxyl radicals, and hydrogen peroxide capable of affecting important biological targets such as DNA (Chedekel and Zeize, 1988) or membrane lipids (Schmitz et al, 1995), acting as UVB and UVA photosensitizer in mammalian skin in vivo (Takeuchi et al 2004). …”

“…Oxygen radicals, and in particular hydrogen peroxide, are considered as intracellular second messengers since they have major roles in cell survival and integrity (Schalreuter et al, 2008). Their level is increased by extracellular ligands such as cytokines (Schreck & Bauerle 1991), ROS act as biologic mediators of UV-induced phosphorylation of membrane receptors (Tyrell, 1994;Schmitz et al, 1995, Peus et al, 1999Girotti, 2001, Kvam & Dahle, 2003; H 2 O 2 is a normal byproduct of the melanogenic pathway (Nappi & Vass, 1996); in several cellular systems, H 2 O 2 acts as an intracellular second messenger for TNFα and TGF (Thannickal & Fanburg, 1995;Chen et al, 1995;Lo et al, 1996); it activates growth factor receptors and in particular those of epidermal growth factor (EGFR) and initiates multiple signaling responses associated with mitogenesis and cell growth regulation (Ulrich & Schlessinger 1990). …”