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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056666-03
Application #
8476985
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$316,350
Indirect Cost
$102,600
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Slominski, Andrzej T; Zmijewski, Michal A; Plonka, Przemyslaw M et al. (2018) How UV Light Touches the Brain and Endocrine System Through Skin, and Why. Endocrinology 159:1992-2007
Slominski, Andrzej T; Hardeland, Ruediger; Zmijewski, Michal A et al. (2018) Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions. J Invest Dermatol 138:490-499
Skobowiat, Cezary; Bro?yna, Anna A; Janjetovic, Zorica et al. (2018) Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo. J Pineal Res 65:e12501
Tuckey, Robert C; Li, Wei; Ma, Dejian et al. (2018) CYP27A1 acts on the pre-vitamin D3 photoproduct, lumisterol, producing biologically active hydroxy-metabolites. J Steroid Biochem Mol Biol 181:1-10
Cheng, Chloe Y S; Kim, Tae-Kang; Jeayeng, Saowanee et al. (2018) Properties of purified CYP2R1 in a reconstituted membrane environment and its 25-hydroxylation of 20-hydroxyvitamin D3. J Steroid Biochem Mol Biol 177:59-69
Tuckey, Robert C; Cheng, Chloe Y S; Slominski, Andrzej T (2018) The serum vitamin D metabolome: What we know and what is still to discover. J Steroid Biochem Mol Biol :
Bro?yna, Anna A; Aplin, Andrew; Cohen, Cynthia et al. (2018) CKS1 expression in melanocytic nevi and melanoma. Oncotarget 9:4173-4187
?niegocka, Martyna; Podg├│rska, Ewa; P?onka, Przemys?aw M et al. (2018) Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy-From Animal Models to Clinical Trials. Int J Mol Sci 19:
Slominski, Andrzej T; Bro?yna, Anna A; Skobowiat, Cezary et al. (2018) On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol 177:159-170
Slominski, Andrzej T; Zmijewski, Michal A; Semak, Igor et al. (2017) Melatonin, mitochondria, and the skin. Cell Mol Life Sci 74:3913-3925

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