In humans, melanin exists as three forms: eumelanin (which is subdivided further into black and brown forms), pheomelanin, and neuromelanin.
Eumelanin and pheomelanin are produced in various amounts in the basal layer of the epidermis within cells called melanocytes. Melanocytes are the mature forms of melanoblasts, which migrate from the neural crest following neural tube closure. As melanin is produced within melanocytes, it is packaged in small, round membrane-bound organelles called melanosomes. Melanosomes are transported from melanocytes to neighboring keratinocytes via tentacle-like dendritic processes. Melanosomes arriving in keratinocytes are positioned superficially to cell nuclei, which serves to protect from incoming ultraviolet (UV) radiation.
The first step of biosynthesis of both eumelanin and pheomelanin begins the same way. Tyrosine is converted into dihydroxyphenylalanine (DOPA), which requires tyrosine hydroxylase and tetrahydrobiopterin as a cofactor. The enzyme tyrosinase then converts dihydroxyphenylalanine into dopaquinone, which can follow a variety of pathways to form the eumelanin or pheomelanin.
The primary stimulus for melanogenesis and subsequent melanosome production is UV radiation, which upregulates melanocyte production of pro-opiomelanocortin (POMC) and its downstream products, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). The overall effect is to increase eumelanin production. (Interestingly, people with pro-opiomelanocortin mutations have red hair and Fitzpatrick skin type 1 due to the relative increase in pheomelanin to eumelanin expression).
Neuromelanin is a dark pigment produced by dopaminergic and noradrenergic cells of the substantia nigra and locus coeruleus as a breakdown product of dopamine.
In its various forms, melanin fulfills a variety of biological functions, including skin and hair pigmentation and photoprotection of the skin and eye.
Pigmentation of the skin results from the accumulation of melanin-containing melanosomes in the basal layer of the epidermis. Differences in skin pigmentation result both from the relative ratio of eumelanin (brown–black) to pheomelanin (yellow–red), as well as the number of melanosomes within melanocytes. Pheomelanin accounts for the pinkish skin constituting the lips, nipples, vagina, and glans of the penis. In general, lightly pigmented skin tends to contain melanocytes with clusters of two to three melanosomes, whereas darkly pigmented skin tends to contain individual melanosomes which can melanize neighboring keratinocytes more readily. The overall melanin density correlates with the darkness of skin as well as Fitzpatrick skin type.
The interplay between melanin and UV radiation is complex. Researchers widely believe that melanin production in melanocytes increased as an evolutionary adaptation to the widespread loss of human body hair more than a million years ago. Populations living closer to the equator tended to develop a greater proportion of eumelanin, which is a UV–absorbent, antioxidant, and free radical scavenger. Conversely, populations living further from the equator are relatively richer in pheomelanin, which produces free radicals in response to UV radiation, accelerating carcinogenesis. As the main stimulus for cutaneous vitamin D production is UV light exposure, it follows that dark-skinned individuals also tend to have lower levels of vitamin D and should be screened accordingly.
Less clear is the link between melanin, the sun, and cutaneous immunology. Both acute and chronic UV light exposure induces immunosuppression; UVA light is used therapeutically for a large number of skin conditions, including psoriasis. Intriguingly, melanin is believed to have immunomodulatory and even anti-bacterial properties, although the underlying mechanisms have not yet been fully elucidated. Malignant melanocytes rich in melanin are less sensitive to chemo-, radio-, or photodynamic therapy, and amelanotic melanomas have longer disease-free and overall survival than melanotic ones. Therefore, some have suggested inhibition of melanogenesis as a therapy for malignant melanoma.
Just as melanin protects the skin from photodamage, it also protects the eye. Melanin is concentrated in the iris and choroid, and those with grey, blue, and green eye colors, as well as albinos, have more sun-related ocular issues.
Hair color is determined by the relative proportion of various forms of melanin:
|||Maranduca MA,Branisteanu D,Serban DN,Branisteanu DC,Stoleriu G,Manolache N,Serban IL, Synthesis and physiological implications of melanic pigments. Oncology letters. 2019 May; [PubMed PMID: 30944614]|
|||Fernandez-Flores A,Saeb-Lima M,Cassarino DS, Histopathology of aging of the hair follicle. Journal of cutaneous pathology. 2019 Apr 1; [PubMed PMID: 30932205]|
|||Starace M,Alessandrini A,Brandi N,Piraccini BM, Use of Nail Dermoscopy in the Management of Melanonychia: Review. Dermatology practical [PubMed PMID: 30775147]|
|||D'Alba L,Shawkey MD, Melanosomes: Biogenesis, Properties, and Evolution of an Ancient Organelle. Physiological reviews. 2019 Jan 1; [PubMed PMID: 30255724]|
|||Del Bino S,Duval C,Bernerd F, Clinical and Biological Characterization of Skin Pigmentation Diversity and Its Consequences on UV Impact. International journal of molecular sciences. 2018 Sep 8; [PubMed PMID: 30205563]|
|||Juhasz MLW,Levin MK, The role of systemic treatments for skin lightening. Journal of cosmetic dermatology. 2018 Dec; [PubMed PMID: 30133125]|
|||Saleem MD, Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome. Pediatric dermatology. 2019 Jan; [PubMed PMID: 30561083]|
|||Carballo-Carbajal I,Laguna A,Romero-Giménez J,Cuadros T,Bové J,Martinez-Vicente M,Parent A,Gonzalez-Sepulveda M,Peñuelas N,Torra A,Rodríguez-Galván B,Ballabio A,Hasegawa T,Bortolozzi A,Gelpi E,Vila M, Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis. Nature communications. 2019 Mar 7; [PubMed PMID: 30846695]|