Trends in Endocrinology & Metabolism
ReviewMelatonin in the skin: synthesis, metabolism and functions
Introduction
The strategic location of the skin as a key barrier between the environment and the internal milieu renders it a crucial instrument of preserving body homeostasis, yet also exposes it to numerous pathological agents, processes and events. Thus, the capability to locally recognize, discriminate and integrate specific signals within a highly heterogeneous environment and to launch appropriate responses immediately is a vital property of the skin [1]. These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems and are in continuous communication with the central immune, neural and endocrine signaling systems 1, 2, 3, 4, 5.
Coordination among these local and systemic responses is mediated by the skin neuroendocrine system 1, 2, which uses local equivalents of the hypothalamo–pituitary–adrenal axis, catecholaminergic, cholinergic, steroidogenic and secosteroidogenic systems. Given their common embryonal origins, it is not surprising that the skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that mammalian skin also harbors a complex melatoninergic system, whose role in the maintenance of cutaneous homeostasis is explored here. Unlike the pineal melatoninergic system, its intracutaneous counterpart is exposed directly to numerous environmental stressors, such as ultraviolet radiation (UVR), the importance of which is reviewed here.
Section snippets
Melatonin biology in a nutshell
Melatonin was isolated from bovine pineal gland almost 50 years ago and was shown to exhibit skin-lightening properties. Its structure was defined as N-acetyl-5-methoxytryptamine [6] (Figure 1). Melatonin is found widely in Nature, where it can be detected in vertebrates, invertebrates, plants, unicellular eukaryotes, algae and even bacteria 7, 8, 9. Melatonin is distributed ubiquitously throughout an organism because its small size and amphiphilic nature facilitate permeability to all cellular
Therapeutic perspectives
A central question in clinical dermatology presently is whether these reported effects of melatonin can be exploited therapeutically, either as a general ‘skin survival factor’ with antigenotoxic properties or as a ‘guardian’ of genome and mitochondrial DNA integrity 18, 36. Of note, melatonin use is not regulated in the USA (i.e. it does not require US FDA approval), having been explored for the treatment of androgenic alopecia [52] and as a component of sunscreens [68]. Melatonin might be
Conclusions
Melatonin and its metabolites are likely to be significant in the local regulatory systems that preserve the physical and functional integrity of the skin. Thus, when activated by environmental stressors or internal dyshomeostatic stimuli, local skin responses are envisaged to counteract or buffer the stressor by recruiting melatonin and its metabolites. In such an intracutaneous stress-response system, melatonin could have an important role through intra-, auto- or para-crine mechanisms. An
Acknowledgements
The paper is dedicated to the memory of Aaron Lerner. Specific reference to many of the excellent original papers not included, because of space restrictions, are, however, cited in comprehensive reviews listed in the reference section.
References (68)
Neuroimmunology of stress: skin takes center stage
J. Invest. Dermatol.
(2006)Differential expression of HPA axis homolog in the skin
Mol. Cell. Endocrinol.
(2007)Identification and characterization of two isozymic forms of arylamine N-acetyltransferase in Syrian hamster skin
J. Invest. Dermatol.
(1993)Metabolism of serotonin to N-acetylserotonin, melatonin, and 5-methoxytryptamine in hamster skin culture
J. Biol. Chem.
(1996)Serotoninergic system in hamster skin
J. Invest. Dermatol.
(2002)Tryptophan hydroxylase (TPH) expression in human skin cells
Biochim. Biophys. Acta
(2003)Conversion of L-tryptophan to serotonin and melatonin in melanoma cells
FEBS Lett.
(2002)Tryptophan hydroxylase-2 controls brain serotonin synthesis
Science
(2004)Pteridines in the control of pigmentation
J. Invest. Dermatol.
(1997)Serotonin metabolism in rat skin: characterization by liquid chromatography-mass spectrometry
Arch. Biochem. Biophys.
(2004)
Natural melatonin ‘knockdown’ in C57BL/6J mice: rare mechanism truncates serotonin N-acetyltransferase
Brain Res. Mol. Brain Res.
Autocrine catecholamine biosynthesis and the beta-adrenoceptor signal promote pigmentation in human epidermal melanocytes
J. Invest. Dermatol.
Melatonin deacetylation: retinal vertebrate class distribution and Xenopus laevis tissue distribution
Brain Res.
Expression of genes coding melatonin and serotonin receptors in rodent skin
Biochim. Biophys. Acta
The effects of the melatonin on ultraviolet-B irradiated cultured dermal fibroblasts
J. Dermatol. Sci.
Identification of the melatonin-binding site MT3 as the quinone reductase 2
J. Biol. Chem.
Hair follicle pigmentation
J. Invest. Dermatol.
Melatonin effect on endothelial cells reduces vascular permeability increase induced by leukotriene B4
Eur. J. Pharmacol.
Neuroendocrinology of the skin
Endocr. Rev.
Controls of hair follicle cycling
Physiol. Rev.
Melanin pigmentation in mammalian skin and its hormonal regulation
Physiol. Rev.
Isolation of melatonin, a pineal factor that lightens melanocytes
J. Am. Chem. Soc.
One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?
J. Pineal Res.
Novel rhythms of N1-acetyl-N2-formyl-5-methoxykynuramine and its precursor melatonin in water hyacinth: importance for phytoremediation
FASEB J.
Melatonin: Nature's most versatile biological signal?
FEBS J.
Melatonin Biosynthesis, Physiological Effects, and Clinical Implications
Pineal melatonin: cell biology of its synthesis and of its physiological interactions
Endocr. Rev.
Molecular pharmacology, regulation and function of mammalian melatonin receptors
Front. Biosci.
Melatonin as an antioxidant: physiology versus pharmacology
J. Pineal Res.
AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice
J. Pineal Res.
Gastrointestinal melatonin: localization, function, and clinical relevance
Dig. Dis. Sci.
Melatonin in cancer management: progress and promise
Cancer Res.
Melatonin in clinical oncology
Neuroendocrinol. Lett.
The cutaneous serotoninergic/melatoninergic system: securing a place under the sun
FASEB J.
Cited by (254)
The cutaneous stress response system in three-spined stickleback and European flounder exposed to oxidative stress: Different mode of action
2023, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyNanophytomedicines: a novel approach for improving therapeutics via delivery of herbal medicine
2023, Advanced Nanoformulations: Theranostic Nanosystems: Volume 3Mechanism of action and promising clinical application of melatonin from a dermatological perspective
2023, Journal of Translational AutoimmunityMelatonin: Potential avenue for treating iron overload disorders
2022, Ageing Research ReviewsAmeliorative effects of topical ramelteon on imiquimod-induced psoriasiform inflammation in mice
2024, Naunyn-Schmiedeberg's Archives of PharmacologyMelatonin as a Promising Agent for Cancer Treatment: Insights into its Effects on the Wnt/beta-catenin Signaling Pathway
2024, Current Medicinal Chemistry