Role of exogenous melatonin in skin biology

描述(申请人提供)：据推测，在脊椎动物中，褪黑素只在松果体和视网膜中产生。然而，越来越多的证据表明，褪黑素在自然界中广泛存在，存在于脊椎动物、无脊椎动物、植物、单细胞真核生物、藻类甚至细菌中。我们已经证明，褪黑素是由哺乳动物的皮肤产生和代谢的，在那里它可以渗透到包括线粒体在内的所有细胞间隔。褪黑素(一种两亲性甲氧基吲哚)具有多种生物活性，作为神经递质、激素、细胞因子和生物反应调节剂，通过与高亲和力受体的相互作用而介导。褪黑素也是一种广谱抗氧化剂，通过不依赖受体的方式发挥作用，它激活细胞保护途径，在高浓度时减弱或抵消氧化应激。其代谢产物N1-乙酰-N2-甲酰基-5-甲氧基犬尿胺(AFMK)也具有这些抗氧化作用，AFMK是褪黑素代谢的最古老产物。因此，褪黑素表现出许多对外皮应激反应系统非常有用的特性。因此，我们提出，皮肤褪黑素能系统通过内分泌、自分泌或旁分泌机制实现细胞特异性的选择性，允许局部抵消或缓冲环境和内源性应激源，以保持皮肤的完整性，而不依赖于松果体褪黑激素的昼夜分泌。这些功能应该包括激活细胞保护和抗凋亡途径，以及抗突变、抗遗传毒性和抗癌活性。褪黑素的生物活性取决于先前存在的局部降解途径和紫外线辐射(UVR)的强度，例如，褪黑素可以通过活性氧或UVB的作用非酶转化为AFMK。因此，我们提出：1.利用体外培养的人表皮角质形成细胞和黑素细胞以及体外组织培养的人皮肤组织块，确定褪黑素对人表皮的保护作用；2.确定褪黑素在调节黑素生成中的作用；3.研究培养的人角质形成细胞和黑素细胞中褪黑素的降解途径。这些目标的实现将决定褪黑素是否可以用于治疗，作为一种具有抗遗传毒性特性的一般“皮肤生存因子”，或者作为基因组和细胞完整性的“守护者”。因此，它可以作为防晒霜的一种成分，或用于治疗色素疾病(如白癜风或色素沉着)、增殖性疾病(包括癌前状态、表皮癌甚至黑色素瘤)、UVB诱导的病理、炎症性皮肤病和皮肤老化。

DESCRIPTION (provided by applicant): 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.