Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions

Abstract

Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage. We also review why melatonin promises to be useful in skin cancer prevention, skin photo- and radioprotection, and as an inducer of repair mechanisms that facilitate the recovery of human skin from environmental damage. The fact that human skin and hair follicles not only express functional melatonin receptors but also engage in substantial, extrapineal melatonin synthesis further encourages one to systematically explore how the skin's melatonin system can be therapeutically targeted in future clinical dermatology and enrolled for preventive medicine strategies.

Figure 1. Targets for melatonin action in skin cells

Melatonin, depending on the concentration, binds to membrane-bound receptor MT1 or MT2. Subsequent activation of signal transduction cascades stimulates the expression of antioxidative enzymes and DNA repair. Melatonin might also be transported to cytoplasm; however, the detailed mechanism is not fully understood. In a cell, melatonin at concentrations higher than 1 nM interacts with the calcium/calmodulin complex, which inhibits NOS1-mediated generation of RNS. On the other hand, melatonin can also interact with NQO2 (previously described as MT3) with potential inhibition of ROS/RNS levels. Recently, peptide transporter PEPT1/2 was found to be responsible for melatonin transport to mitochondria (Huo et al., 2017). Melatonin improves mitochondrial membrane potential (Δψ_m) by inhibition of the mitochondrial permeability transition pore (MPTP) and stimulation of uncoupling proteins (UCPs). This results in an elevated production of ATP by oxidative phosphorylation (OXIPHOS). These effects will also depend on its local synthesis (tryptophan (Trp) → serotonin (5TH) → melatonin (Mlt)) and metabolism. NQO2, quinone reductase 2; ROS, reactive oxygen species, RNS, reactive nitrogen species.

Figure 2. Topically or orally administered melatonin affects different skin functions

To compensate inadequate intracutaneous levels of melatonin secondary to environmentally induced degradation or suboptimal local production or transport from the pineal gland, melatonin can be delivered to the skin via different routes. Orally ingested melatonin is rapidly metabolized in the liver by CYP450 into 6-hydroxymelatonin while sublingual (transmucosal) melatonin administration can bypass liver metabolism. Transdermal application of melatonin appears to be optimal for local application due to slow absorption, deposition in the skin, lack of identifiable site effects, and availability of different formulations (Flo et al., 2016, 2017; Milan et al., 2017; Romic et al., 2016; Scheuer et al., 2016b; Zetner et al., 2016). Because there is a cutaneous melatonin metabolism with metabolites sharing similar activities as melatonin (Slominski et al., 2017b), the effects summarized in the central column may also be secondary to the action of its metabolites. Of note, 6-hydroxymelatonin, 4-hydroxymelatonin, 2-hydroxymelatonin, AFMK, or AMK being produced by different species, in addition to the human body, may fulfill the definition of natural products for topical applications to improve healthy skin status. Importantly, the functional effects depicted here may also be exerted by endogenous melatonin synthesized in the skin and hair follicles (see main text). AFMK, N¹-acetyl-N²-formyl-5-methoxykynuramine; AMK, N¹-acetyl-5-methoxykynuramine; CYP, cytochrome P450.