It was assumed that in vertebrates melatonin is only produced in the pineal gland and retina. However, evidence has accumulated that melatonin is widely detectable throughout Nature, being found in vertebrates, invertebrates, plants, unicellular eukaryotes, algae and even bacteria. We have documented that melatonin is produced and metabolized by the mammalian skin, where it can permeate to all cellular compartments including mitochondria. Melatonin (an amphilic methoxyindole) has pleiotropic bioactivities, as neurotransmitter, hormone, cytokine and biological response modifier, which are mediated by interactions with high affinity receptors. Melatonin is also a broad-spectrum antioxidant and acting via receptor-independent manner it activates cytoprotective pathways and at high concentrations it attenuates or counteracts the oxidative stress. These antioxidant effects are also shared by its metabolite, N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK), phylogenetically the oldest product of melatonin metabolism. Thus, melatonin exhibits a number of properties that are extremely useful for the integumental stress-response systems. Accordingly, we have proposed that the cutaneous melatoninergic system enables for cell-specific selectivity through intra-, auto- or paracrine mechanisms, which allow locally counteracting or buffering both environmental and endogenous stressors to maintain skin integrity, independent of circadian pineal melatonin secretion. Such functions should include activation of cytoprotective and anti-apoptotic pathways, and antimutagenic, antigenotoxic and anticancerogenic activites. Melatonin bioactivity would depend on preexistent local degradative pathways and the intensity of exposure to ultraviolet radiation (UVR), e.g., melatonin can be converted non-enzymatically to AFMK through action of reactive oxygen species or UVB. Therefore, we are proposing: 1. To define the protective role of melatonin in human epidermis using epidermal keratinocytes and melanocytes cultured in vitro and human skin explants histocultured ex-vivo;2. To define the role of melatonin in regulation of melanogenesis;3. To characterize the pathway of melatonin degradation in cultured human keratinocytes and melanocytes. Realization of these aims will define whether melatonin can be exploited therapeutically, either as a general """"""""skin survival factor"""""""" with anti- genotoxic properties or as a """"""""guardian"""""""" of genome and cellular integrity. Thus, it may be used as a component of sunscreens or in the treatment of pigmentary diseases (e.g. vitiligo or hyperpigmentation), proliferative processes (including precancerous states, epidermal cancer or even melanoma), UVB-induced pathology, inflammatory dermatoses and skin aging.

Public Health Relevance

A long-standing clinically and economically important key question is whether melatonin and its metabolites, that have been shown experimentally to serve as a """"""""guardians"""""""" of genome and cellular integrity, can be exploited therapeutically as a general """"""""skin protectants"""""""" with anti-genotoxic, anti-oxidant, and/or anti- carcinogenic properties. The systematic dissection of intracutaneous melatonin metabolism and direct melatonin actions will define novel therapeutic strategies for UVB-induced skin pathology and for the exploitation of melatonin as a protective or cosmetic agent.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Tseng, Hung H
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University of Tennessee Health Science Center
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Slominski, Andrzej T; Bro?yna, Anna A; Zmijewski, Michal A et al. (2017) Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. Lab Invest 97:706-724
Tarasen, Ashley; Carlson, J Andrew; Leonard, M Kathryn et al. (2017) Pigmented Epithelioid Melanocytoma (PEM)/Animal Type Melanoma (ATM): Quest for an Origin. Report of One Unusual Case Indicating Follicular Origin and Another Arising in an Intradermal Nevus. Int J Mol Sci 18:
Janjetovic, Zorica; Jarrett, Stuart G; Lee, Elizabeth F et al. (2017) Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways. Sci Rep 7:1274
Cheng, Chloe Y S; Kim, Tae-Kang; Jeayeng, Saowanee et al. (2017) Properties of purified CYP2R1 in a reconstituted membrane environment and its 25-hydroxylation of 20-hydroxyvitamin D3. J Steroid Biochem Mol Biol :
Slominski, Andrzej T; Bro?yna, Anna A; Tuckey, Robert C (2017) Cutaneous Glucocorticoidogenesis and Cortisol Signaling Are Defective in Psoriasis. J Invest Dermatol 137:1609-1611
Slominski, Andrzej T; Bro?yna, Anna A; Skobowiat, Cezary et al. (2017) On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol :
Slominski, Andrzej T; Kim, Tae-Kang; Hobrath, Judith V et al. (2017) Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. Sci Rep 7:11434
Slominski, Andrzej T; Zmijewski, Michal A (2017) Glucocorticoids Inhibit Wound Healing: Novel Mechanism of Action. J Invest Dermatol 137:1012-1014
Slominski, Andrzej T; Zmijewski, Michal A; Semak, Igor et al. (2017) Melatonin, mitochondria, and the skin. Cell Mol Life Sci 74:3913-3925
Lin, Zongtao; Chen, Hao; Belorusova, Anna Y et al. (2017) 1?,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis. Sci Rep 7:10193

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