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 #
5R01AR056666-04
Application #
8675728
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
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$326,340
Indirect Cost
$105,840
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
Skobowiat, Cezary; Slominski, Andrzej T (2015) UVB Activates Hypothalamic-Pituitary-Adrenal Axis in C57BL/6 Mice. J Invest Dermatol 135:1638-48
Slominski, Andrzej T; Carlson, J Andrew (2014) Melanoma resistance: a bright future for academicians and a challenge for patient advocates. Mayo Clin Proc 89:429-33
Slominski, A; Kim, T-K; Bro?yna, A A et al. (2014) The role of melanogenesis in regulation of melanoma behavior: melanogenesis leads to stimulation of HIF-1? expression and HIF-dependent attendant pathways. Arch Biochem Biophys 563:79-93
Slominski, Andrzej T; Kim, Tae-Kang; Takeda, Yukimasa et al. (2014) ROR? and ROR ? are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J 28:2775-89
Slominski, Andrzej T; Zmijewski, Michal A; Semak, Igor et al. (2014) Cytochromes p450 and skin cancer: role of local endocrine pathways. Anticancer Agents Med Chem 14:77-96
Zhu, Guo; Janjetovic, Zorica; Slominski, Andrzej (2014) On the role of environmental humidity on cortisol production by epidermal keratinocytes. Exp Dermatol 23:15-7
Bro?yna, Anna A; Jó?wicki, Wojciech; Slominski, Andrzej T (2014) Decreased VDR expression in cutaneous melanomas as marker of tumor progression: new data and analyses. Anticancer Res 34:2735-43
Slominski, Andrzej T; Kim, Tae-Kang; Shehabi, Haleem Z et al. (2014) In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. Mol Cell Endocrinol 383:181-92
Janjetovic, Zorica; Nahmias, Zachary P; Hanna, Sherie et al. (2014) Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes. J Pineal Res 57:90-102
Tuckey, Robert C; Slominski, Andrzej T; Cheng, Chloe Y S et al. (2014) Lumisterol is metabolized by CYP11A1: discovery of a new pathway. Int J Biochem Cell Biol 55:24-34

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