INTRODUCTION
With ultraviolet radiation causing skin aging and skin cancer, the use of melanotropic peptides are slowly becoming more popular as consumers are looking for alternative ways to obtain a facultative tan.1 The products are unregulated and can be obtained through the internet, gyms and tanning salons. They are marketed as ‘Melanotans,’ which can induce skin tanning.
However, there is only one regulated alpha-MSH analog known as afamelanotide ([Nle4-D-Phe7]-alpha-MSH), which is a photo protective compound.2 Afamelanotide was approved in Italy in 2010 and in Switzerland in 2012 for patients who are diagnosed with erythropoietic protoporphyria (EPP). Afamelanotide has successfully completed phase II and III clinical trials in Europe and in the US in patients with phototoxicity disorders including EPP, polymorphic light eruption (PLE), vitiligo, prevention of and actinic keratoses (AK) and squamous cell carcinoma (SCC) in organ transplant recipients.2
Alpha Melanocyte Stimulating Hormone (Alpha-MSH), Melanogenesis & Melanocortin 1 Receptor (MC1R)
Alpha melanocyte stimulating hormone (Alpha-MSH) is a tridecapeptide pigmentary hormone that is 13 amino acids in length and is synthesized from 2 sources: the pituitary gland and skin.3 Alpha-MSH is synthesized by endoproteolytic decomposition of propiomelanocortin (POMC) (Figure 1). In the skin, the hormone is synthesized in keratinocytes, melanocytes, and macrophages upon exposure to UV radiation.4 UVR increases alpha-MSH release by keratinocytes as it directly causes DNA damage in epidermal cells. Keratinocytes synthesize alpha-MSH through a p53 mediated mechanism which in turn induces tanning.1,5,6 Alpha-MSH may play a role by either promoting apoptosis or, by promoting nuclear repair processes.14 Alpha-MSH binds to the melanocortin-1 receptor (MC1R) that is present in dermal cells including melanocytes, keratinocytes, endothelial cells, skin fibroblasts and mast cells.7,8 MC1R is not expressed in melanocyte stem cells, or melanoblasts.9 When MC1R is stimulated, melanogenesis occurs by increasing tyrosinase activity and increasing melanocyte proliferation.10,11 Physiologic alpha-MSH released from keratinocytes acts locally on adjacent melanocytes via a paracrine mechanism and on themselves via an autocrine mechanism.12
The alpha-MSH binds the G protein coupled MC1R.13 This in turn activates adenylate cyclase which forms cAMP from ATP. The newly formed cAMP stimulates protein kinase A, which triggers cAMP-responsive element binding protein (CREB). CREB binds the promoter of the micropthalmia-associated transcription factor (MITF) and activates its synthesis. MITF induces the gene for tyrosinase, which is the rate limiting enzyme for melanin formation.14 After alpha-MSH binds to melanocytes, melanogenesis is activated and an increase in the melanogenic enzyme, tyrosinase, occur and further melanin synthesis is stimulated.15,16
The process of melanogenesis is as follows: L-phenylalanine is metabolized by phenylalanine hydroxylase into L-tyrosine. This is then further metabolized by tyrosine hydroxylase into L-Dopa. Tyrosinase acts on L-dopa to form dopaquinone. Dopaquinone produces several variants of melanin, two of which are eumelanin and pheomelanin.16 Pheomelanin is a yellow to red pigment and eumelanin is a sulfur-free, brown black pigment. Pheomelanin is the non-effective epidermal pigment that is highly reactive
