The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a “guardian” of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging.

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‐methoxy‐tryptamine (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 V _max = 63.7 ng/10 ⁶ cells and K _m = 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.—Kim, T.‐K., Kleszczyński, K., Janjetovic, Z., Sweatman, T., Lin, Z., Li, W., Reiter, R. J., Fischer, T. W., Slominski, A. T. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J. 27, 2742‐2755 (2013). www.fasebj.org

The skin, being the largest organ in the human body, is exposed to the environment and suffers from both intrinsic and extrinsic aging factors. The skin aging process is characterized by several clinical features such as wrinkling, loss of elasticity, and rough-textured appearance. This complex process is accompanied with phenotypic and functional changes in cutaneous and immune cells, as well as structural and functional disturbances in extracellular matrix components such as collagens and elastin. Because skin health is considered one of the principal factors representing overall “well-being” and the perception of “health” in humans, several anti-aging strategies have recently been developed. Thus, while the fundamental mechanisms regarding skin aging are known, new substances should be considered for introduction into dermatological treatments. Herein, we describe melatonin and its metabolites as potential “aging neutralizers”. Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. It regulates circadian rhythmicity and also exerts anti-oxidative, anti-inflammatory, immunomodulatory, and anti-tumor capacities. The intention of this review is to summarize changes within skin aging, research advances on the molecular mechanisms leading to these changes, and the impact of the melatoninergic anti-oxidative system controlled by melatonin and its metabolites, targeting the prevention or reversal of skin aging.

Melatonin is produced in almost all living taxa and is probably 2‐3 billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non‐enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O‐demethylation or non‐enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor‐dependent and receptor‐independent mechanisms, receptors for melatonin metabolites remain to be identified, while their receptor‐independent activities are well documented. The human skin with its main cellular components including malignant cells can both produce and rapidly metabolize melatonin in cell‐type and context‐dependent fashion. The predominant metabolism in human skin occurs through indolic, CYP‐mediated and kynuric pathways with main metabolites represented by 6‐hydroxymelatonin, N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK), N¹‐acetyl‐5‐methoxykynuramine (AMK), 5‐methoxytryptamine, 5‐methoxytryptophol and 2‐hydroxymelatonin. AFMK, 6‐hydroxymelatonin, 2‐hydroxymelatonin and probably 4‐hydroxymelatonin can potentially be produced in epidermis through UVB‐induced non‐enzymatic melatonin transformation. The skin metabolites are also the same as those produced in lower organisms and plants indicating phylogenetic conservation across diverse species and adaptation by skin of the primordial defense mechanism. As melatonin and its metabolites counteract or buffer environmental stresses to maintain its homeostasis through broad‐spectrum activities, both melatoninergic and degradative pathways must be precisely regulated, because the nature of phenotypic regulations will depend on local concentration of melatonin and its metabolites. These can be receptor‐mediated or represent non‐receptor regulatory mechanisms.