title: Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells.
abstract: Indolic and kynuric pathways of skin melatonin metabolism were monitored by liquid chromatography mass spectrometry in human keratinocytes, melanocytes, dermal fibroblasts, and melanoma cells. Production of 6-hydroxymelatonin [6(OH)M], N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and 5-methoxytryptamine (5-MT) was detected in a cell type-dependent fashion. The major metabolites, 6(OH)M and AFMK, were produced in all cells. Thus, in immortalized epidermal (HaCaT) keratinocytes, 6(OH)M was the major product with Vmax = 63.7 ng/10(6) cells and Km = 10.2 μM, with lower production of AFMK and 5-MT. Melanocytes, keratinocytes, and fibroblasts transformed melatonin primarily into 6(OH)M and AFMK. In melanoma cells, 6(OH)M and AFMK were produced endogenously, a process accelerated by exogenous melatonin in the case of AFMK. In addition, N-acetylserotonin was endogenously produced by normal and malignant melanocytes. Metabolites showed selective antiproliferative effects on human primary epidermal keratinocytes in vitro. In ex vivo human skin, both melatonin and AFMK-stimulated expression of involucrin and keratins-10 and keratins-14 in the epidermis, indicating their stimulatory role in building and maintaining the epidermal barrier. In summary, the metabolism of melatonin and its endogenous production is cell type-dependent and expressed in all three main cell populations of human skin. Furthermore, melatonin and its metabolite AFMK stimulate differentiation in human epidermis, indicating their key role in building the skin barrier.
authors.affiliation: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.forename: Konrad
authors.initials: K
authors.lastname: Kleszczynski
authors.forename: Zorica
authors.initials: Z
authors.lastname: Janjetovic
authors.forename: Trevor
authors.initials: T
authors.lastname: Sweatman
authors.forename: Zongtao
authors.initials: Z
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Tobias W
authors.initials: TW
authors.lastname: Fischer
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
mesh_terms: D008735:5-Methoxytryptamine / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D053550:Keratin-10 / Q000378:metabolism; D053547:Keratin-14 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D007735:Kynuramine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008550:Melatonin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D053858:Metabolic Networks and Pathways; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D013552:Swine
chemical_list: D053547:Keratin-14; D053550:Keratin-10; D012701:Serotonin; D007735:Kynuramine; D008735:5-Methoxytryptamine; C041550:N-acetyl-N-formyl-5-methoxykynurenamine; D008550:Melatonin; C006389:N-acetylserotonin; C012365:6-hydroxymelatonin
keywords: 5-methoxytryptamine; 6-hydroxymelatonin; AFMK; keratinocytes; melanocytes