Metabolism of melatonin in the skin: Why is it important?
Metabolism of melatonin in the skin: Why is it important?
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DOI：
10.1111/exd.13208
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发表时间：
2017-07
影响因子：
3.6
通讯作者：
Reiter RJ
中科院分区：
文献类型：
--
作者：
Slominski AT;Semak I;Fischer TW;Kim TK;Kleszczyński K;Hardeland R;Reiter RJ
褪黑激素在几乎所有的生物类群中产生，并且可能有20 - 30亿年的历史。其多效性活性与其局部浓度有关，其局部浓度仅次于其局部合成、从远处递送以及代谢或非酶消耗。这种消耗通过吲哚、犬尿酸和细胞色素P450（CYP 1A 1）介导的羟基化和O-去甲基化或非酶促过程产生代谢产物，具有潜在的不同表型效应。虽然褪黑激素通过受体依赖性和非依赖性机制发挥作用，但褪黑激素代谢物的受体仍有待鉴定，而其受体非依赖性活性已得到充分证明。人类皮肤的主要细胞成分包括恶性细胞，可以以细胞类型和环境依赖的方式产生和快速代谢褪黑激素。人皮肤中的主要代谢通过吲哚、CYP介导和犬尿途径发生，主要代谢物由6-羟基褪黑激素、N1-乙酰基-N2-甲酰基-5-甲氧基犬尿胺（AFMK）、N1-乙酰基-5-甲氧基犬尿胺（AMK）、5-甲氧基色胺、5-甲氧基胆甾醇和2-羟基褪黑激素代表。AFMK、6-羟基褪黑素、2-羟基褪黑素和可能的4-羟基褪黑素可以通过UVB诱导的非酶促褪黑素转化在表皮中产生。皮肤代谢产物也与低等生物和植物中产生的代谢产物相同，表明不同物种的系统发育保守性和皮肤对原始防御机制的适应性。由于褪黑激素及其代谢物通过广谱活性抵消或缓冲环境应激以维持其稳态，因此必须精确调节褪黑激素能和降解途径，因为褪黑激素及其代谢物的局部浓度将决定表型调节的性质。这些可以是受体介导的或代表非受体调节机制。
Melatonin is produced in almost all living taxa and is probaly 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 independent mechanism, 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. Since 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 local concentration of melatonin and its metabolites will decide about the nature of phenotypic regulations. These can be receptor mediated or represent non-receptor regulatory mechanisms.