Human skin is repeatedly exposed to UVR that influences the function and survival of many cell types and is regarded as the main causative factor in the induction of skin cancer. It has been traditionally believed that skin pigmentation is the most important photoprotective factor, as melanin, besides functioning as a broadband UV absorbent, has antioxidant and radical scavenging properties. Besides, many epidemiological studies have shown a lower incidence for skin cancer in individuals with darker skin compared to those with fair skin. Skin pigmentation is of great cultural and cosmetic importance, yet the role of melanin in photoprotection is still controversial. This article outlines the major acute and chronic effects of UVR on human skin, the properties of melanin, the regulation of pigmentation and its effect on skin cancer prevention.

All organisms, from simple invertebrates to complex human beings, exist in different colors and patterns, which arise from the unique distribution of pigments throughout the body. Pigmentation is highly heritable, being regulated by genetic, environmental, and endocrine factors that modulate the amount, type, and distribution of melanins in the skin, hair, and eyes. In addition to its roles in camouflage, heat regulation, and cosmetic variation, melanin protects against UV radiation and thus is an important defense system in human skin against harmful factors. Being the largest organ of the body that is always under the influence of internal and external factors, the skin often reacts to those agents by modifying the constitutive pigmentation pattern. The focus of this review is to provide an updated overview of important physiological and biological factors that increase pigmentation and the mechanisms by which they do so. We consider endocrine factors that induce temporary (e.g., during pregnancy) or permanent (e.g., during aging) changes in skin color, environmental factors (e.g., UV), certain drugs, and chemical compounds, etc. Understanding the mechanisms by which different factors and compounds induce melanogenesis is of great interest pharmaceutically (as therapy for pigmentary diseases) and cosmeceutically (e.g., to design tanning products with potential to reduce skin cancer risk).

Visible pigmentation in mammals results from the synthesis and distribution of melanin in the skin, hair bulbs, and eyes. The melanins are produced in melanocytes and can be of two basic types: eumelanins, which are brown or black, and phaseomelanins, which are red or yellow. In mammals typically there are mixtures of both types. The most essential enzyme in this melanin biosynthetic pathway is tyrosinase and it is the only enzyme absolutely required for melanin production. However, recent studies have shown that mammalian melanogenesis is not regulated solely by tyrosinase at the enzymatic level, and have identified additional melanogenic factors that can modulate pigmentation in either a positive or negative fashion. In addition, other pigment-specific genes that are related to tyrosinase have been cloned which encode proteins that apparently work together at the catalytic level to specify the quantity and quality of the melanins synthesized. Future research should provide a greater understanding of the enzymatic interactions, processing, and tissue specificity that are important to pigmentation in mammals.

More than 150 genes have been identified that affect skin color either directly or indirectly, and we review current understanding of physiological factors that regulate skin pigmentation. We focus on melanosome biogenesis, transport and transfer, melanogenic regulators in melanocytes and factors derived from keratinocytes, fibroblasts, endothelial cells, hormones, inflammatory cells and nerves. Enzymatic components of melanosomes include tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase, which depend on the functions of OA1, P, MATP, ATP7A and BLOC-1 to synthesize eumelanins and pheomelanins. The main structural component of melanosomes is Pmel17/gp100/Silv, whose sorting involves adaptor protein 1A (AP1A), AP1B, AP2 and spectrin, as well as a chaperone-like component, MART-1. During their maturation, melanosomes move from the perinuclear area toward the plasma membrane. Microtubules, dynein, kinesin, actin filaments, Rab27a, melanophilin, myosin Va and Slp2-a are involved in melanosome transport. Foxn1 and p53 up-regulate skin pigmentation via bFGF and POMC derivatives including α-MSH and ACTH, respectively. Other critical factors that affect skin pigmentation include MC1R, CREB, ASP, MITF, PAX3, SOX9/10, LEF-1/TCF, PAR-2, DKK1, SCF, HGF, GM-CSF, endothelin-1, prostaglandins, leukotrienes, thromboxanes, neurotrophins and neuropeptides. UV radiation up-regulates most factors that increase melanogenesis. Further studies will elucidate the currently unknown functions of many other pigment genes/proteins.

Visible pigmentation of the skin, hair, and eyes depends primarily on the functions of melanocytes, a very minor population of cells that specialize in the synthesis and distribution of the pigmented biopolymer melanin. Melanocytes are derived from precursor cells (called melanoblasts) during embryological development, and melanoblasts destined for the skin originate from the neural crest. The accurate migration, distribution, and functioning of melanoblasts/melanocytes determine the visible phenotype of organisms ranging from simple fungi to the most complex animal species. In human skin, melanocytes are localized at the dermal/epidermal border in a characteristic regularly dispersed pattern. Each melanocyte at the basal layer of the epidermis is functionally connected to underlying fibroblasts in the dermis and to keratinocytes in the overlying epidermis. Those three types of cells are highly interactive and communicate with each other via secreted factors and their receptors and via cell/cell contacts to regulate the function and phenotype of the skin. Overview: Architecture of the SkinEpidermal melanocytes occur at an approximate ratio of 1:10 among basal keratinocytes and distribute the melanin they produce to ϳ40 overlying suprabasal keratinocytes via their elongated dendrites and cell/cell contacts (presented schematically in Fig. 1). Although melanocytes and stem cell keratinocytes in the basal layer of the epidermis are very stable populations that proliferate extremely slowly under normal circumstances, keratinocytes in the upper layers of the epidermis proliferate relatively rapidly. That upward pressure carries them toward the surface of the skin along with their ingested melanin to form a critical barrier for the organism against the environment and the many stresses that originate there. Thus it is not the melanin within melanocytes only, but in combination with the pigment in more superficial layers, that gives skin its characteristic color. Although melanocytes in other locations of the body (e.g. hair follicles, eyes, inner ear, etc.) interact with surrounding cells in manners distinct from those in the epidermis, the basic processes involved in producing the melanin and the organelles within which it is synthesized (termed melanosomes) are comparable, as are the factors that regulate melanogenesis. This review will restrict itself to epidermal pigmentation, and readers interested in factors influencing pigmentation at other sites should consult recent reviews (1-6) and books (7, 8) on those topics.

DNA damage induced by UV radiation is a critical event in skin photocarcinogenesis. However, the role of racial/ethnic origin in determining individual UV sensitivity remains unclear. In this study, we examined the relationships between melanin content and DNA damage induced by UV exposure in situ in normal human skin of different racial/ethnic groups, phototypes, and UV sensitivities. The minimal erythema dose (MED) was established for each subject exposed to UVA/UVB radiation, and skin was biopsied before as well as 7 min, 1 day, and 1 wk after UV exposure. There was great variation among individuals in the amount of DNA damage incurred and rates of its removal. The results show that after exposure to 1 MED of UV, the skin of subjects from all groups suffered significant DNA damage, and that increasing content of constitutive melanin inversely correlated with the amount of DNA damage. It is clear from these results that measured erythemal UV sensitivity of the skin (MED) is a more useful predictor of DNA photodamage than is racial/ethnic origin or skin phototype and that rates of DNA damage removal following UV radiation may be the critical determinant of the UV sensitivity (including predisposition to cancer) of the skin.

The production of melanin pigment in mammals requires tyrosinase, an enzyme which hydroxylates the amino acid tyrosine to DOPA (3,4‐dihydroxyphenylalanine), thus allowing the cascade of reactions necessary to synthesize that biopolymer. However, there are other regulatory steps that follow the action of tyrosinase and modulate the quantity and quality of the melanin produced. DOPAchrome tautomerase is one such melanogenic enzyme that isomerizes the pigmented intermediate DOPAchrome to DHICA (5,6‐dihydroxyindole‐2‐carboxylic acid) rather than to DHI (5,6‐dihydroxyindole), which would be generated spontaneously. This enzyme thus regulates a switch that controls the proportion of carboxylated subunits in the melanin biopolymer. Efforts to clone the gene for tyrosinase have resulted in the isolation of a family of tyrosinase related genes which have significant homology and encode proteins with similar predicted structural characteristics. Using specific antibodies generated against synthetic peptides encoded by unique areas of several of those proteins, we have immuno‐affinity purified them and studied their melanogenic catalytic functions. We now report that TRP‐2 (tyrosinase related protein‐2), which maps to and is mutated at the slaty locus in mice, encodes a protein with DOPAchrome tautomerase activity.

Several genes critical to the enzymatic regulation of melanin production in mammals have recently been cloned and mapped to the albino, brown and slaty loci in mice. All three genes encode proteins with similar structures and features, but with distinct catalytic capacities; the functions of two of those gene products have previously been identified. The albino locus encodes tyrosinase, an enzyme with three distinct melanogenic functions, while the slaty locus encodes tyrosinase‐related protein 2 (TRP2), an enzyme with a single specific, but distinct, function as DOPAchrome tautomerase. Although the brown locus, encoding TRP1, was actually the first member of the tyrosinase gene family to be cloned, its catalytic function (which results in the production of black rather than brown melanin) has been in general dispute. In this study we have used two different techniques (expression of TRP1 in transfected fibroblasts and immunoaffinity purification of TRP1 from melanocytes) to examine the enzymatic function(s) of TRP1. The data demonstrate that the specific melanogenic function of TRP1 is the oxidation of 5,6‐dihydroxyindole‐2‐carboxylic acid (DHICA) to a carboxylated indole‐quinone at a down‐stream point in the melanin biosynthetic pathway. This enzyme activity appears to be essential to the further metabolism of DHICA to a high molecular weight pigmented biopolymer.