Increased Eumelanin Expression and Tanning is Induced by a Superpotent Melanotropin [Nle4-d-Phe7]-α-MSH in Humans¶

Abstract

Seven normal volunteers (six males and one female) with tanning skin types III or IV (Fitzpatrick scale) were given 10 daily subcutaneous injections of a superpotent synthetic analog of alpha-melanocyte stimulating hormone (alpha-MSH) over two weeks. This agent, [Nle4-D-Phe7]alpha-MSH, also called Melanotan-I (MT-I), was administered at a dose of 0.16 mg/kg/day (Monday-Friday), over a two week period. Tanning was measured serially using computerized light reflectance. This regimen induced tanning at 3 of 8 anatomic sites including the face, neck and forearm by comparison of baseline to (1) the end of the daily dosing period, (day 14), and (2) one week later, (day 21). Shave biopsies of the forearm taken at baseline and day 21 were analyzed by high performance liquid chromatography for eumelanin content which was measured as the permanganate oxidation product, pyrrole-2,3,5-tricarboxylic acid or PTCA. Pheomelanin content was measured as the hydroiodic acid digestion product, aminohydroxyphenylalanine (AHP). Eumelanin was also measured in the forehead skin samples of three subjects. The HPLC results show that mean (+/- SD) baseline eumelanin (PTCA) levels in forehead skin (n = 3) averaged 1.38 (+/- 0.87) ng/mg of wet skin tissue weight. Higher mean baseline levels of PTCA were detected in forearm skin (2.06 +/- 0.28 ng/mg wet weight, n = 7). One week after MT-I treatments ended, there was a mean (SD) 49% (+/- 17.6%) increase in forehead skin PTCA levels compared to baseline (P = 0.019, n = 3, by paired sample T-test). The mean (SD) increase in forearm skin PTCA levels was 98% (+/- 25.4%) over the same period (P = 0.003). In contrast, forearm pheomelanin expression following MT-I treatment did not significantly change from baseline. Overall, the MT-I regimen increased the eumelanin: pheomelanin ratio in forearm skin from 51:1 at baseline to 86:1 following MT-I (P = 0.054 by paired sample T-test). These results show that the tanning induced by MT-I in the face and forearm is associated with a significant increase in the eumelanin content of the human skin.

Advances in the management of erythropoietic protoporphyria – role of afamelanotide

“…First demonstrated to induce skin pigmentation and tanning in the early 1990s, afamelanotide increases eumelanin density in normal subjects as well as patients with EPP or XLPP 40–43. In normal volunteers, afamelanotide administration at a dose of 0.16 mg/kg/d subcutaneously induced tanning with an increase in the eumelanin: pheomelanin ratio in the absence of sun exposure ( p =0.054), accompanied by significant increases in eumelanin at different anatomical sites 40.…”

“…When the MC1R is stimulated by α-MSH, melanin synthesis transitions from the less protective yellow-red pheomelanin to more protective brown-black eumelanin 33,38–40. Eumelanin provides photoprotection by absorbing and scattering visible and ultraviolet (UV) light, scavenging free radicals and reactive oxygen species, and functioning as a neutral density filter capable of equal reduction of transmission of all wavelengths of light 33,34,39,41.…”

“…Eumelanin provides photoprotection by absorbing and scattering visible and ultraviolet (UV) light, scavenging free radicals and reactive oxygen species, and functioning as a neutral density filter capable of equal reduction of transmission of all wavelengths of light 33,34,39,41. Afamelanotide stimulates eumelanin synthesis independent of exposure to UV radiation, as opposed to endogenous α-MSH, which is produced in response to UV damaged skin cells to prevent further damage 40,41…”

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

“…In the process, investigators developed potent and receptor-selective agonists and antagonists that can be used for medical applications. This research has led to human clinical trials at the College of Medicine at the University of Arizona (57–60) and elsewhere.…”

Activation of Molecular Adaptation to Sunlight—A New Approach to Photoprotection

“…UVB initiates production of a melanocyte stimulating hormone (a-MSH) along with other paracrine factors from cutaneous keratinocytes and melanocytes, which leads to increased melanin production (Gilchrest and Eller, 1999). Synthetic potent derivatives of a-MSH are being developed to increase tanning in humans without the need for sunlight exposure as an approach to activating this photoadaptive response in order to protect from sun damage (Dorr et al, 2000). Thymine dimers, one of the forms of DNA damage caused by UV exposure, are able to activate p53, increase DNA repair, and induce melanization.…”