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The Pineal Gland and Melatonin
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Jerry Vriend, Nancy A.M. Alexiuk
It has been estimated that during a single pass through the liver, 90% of blood melatonin is cleared.246 Melatonin is metabolized in the liver to 6-hydroxymelatonin; this metabolite is conjugated primarily with sulfate (but a small percentage is also conjugated to glucuronide) and excreted in the urine.242,247,248 In rats 6-sulfatoxymelatonin levels increase in urine 2 to 5 h after the onset of darkness.249 In the mammalian brain melatonin may be converted to N-acetyl-5-methoxykynurenamine.250
Shy-Drager Syndrome and Multiple System Atrophy
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
The pineal gland releases melatonin in a diurnal pattern that is under control by an endogenous circadian oscillator located in the suprachiasmatic nucleus. Light appears to play a major role in determining the rhythm and its effects are mediated through retinohypothalamic projections. Pineal innervation is derived from the superior cervical ganglion which is supplied by preganglionic fibres arising from the ILC. Nocturnal stimulation of the β-adrenergic pineal receptors results in enhanced synthesis and release of melatonin. Following rapid metabolism, 6-hydroxymelatonin is conjugated and excreted in the urine. Normal subjects excrete most of the urinary 6-hydroxymelatonin at night and relatively little during the day (Tetsuo et al., 1981). In PAF, the total amount excreted each day is low but the diurnal pattern is preserved. The main abnormality in MSA is a disruption in the pattern: many patients excrete as much 6-hydroxymelatonin in the day as at night. Central nervous system lesions in MSA presumably interfere with the pathways controlling melatonin secretion.
Melatonin: A “Guardian” of the Genome and Cellular Integrity for Prevention of Photocarcinogenesis
Published in Andreia Ascenso, Sandra Simões, Helena Ribeiro, Carrier-Mediated Dermal Delivery, 2017
Patricia Manteigas, Andreia Ascenso
The classical pathway for melatonin degradation starts with circulating melatonin being metabolized mainly in the liver by the CYP450 family enzymes (CYP1A2, CYP1A1 and, to a lesser extent, by CYP1B1) to 6-hydroxymelatonin (the main product of this pathway) [36,45]. Then, it becomes more polarized by the addition of either sulfate (6-sulfatoxymelatonin) or glucuronide (extremely limited) facilitating its excretion process. Although it was initially thought that melatonin was catabolized to 6(OH)M exclusively in the liver, recent evidence indicates that some 6(OH)M may be formed at extrahepatic sites, namely in the skin [31]. The metabolism in extrahepatic tissues exhibits substantial differences, such as the prevalence of the classical, indolic, or kynuric pathways depending on the tissue. In the brain, a substantial fraction of melatonin is metabolized to kynuramine derivatives, for example [46].
Exploring the effects of large-area dorsal skin irradiation on locomotor activity and plasm melatonin level in C3H/He mice
Published in Chronobiology International, 2021
Xuewei Fan, Zeqing Chen, Wenqi Li, Haokuan Qin, Shijie Huang, Zhicheng Lu, Yinghua Li, Muqing Liu
In addition to the clock phase shift effect, light can also acutely change the level of physiological and behavioral parameters (Redlin 2001; Ruger et al. 2003). A typical example is that a certain intensity of light can rapidly reduce the melatonin levels in mammals (Deveson et al. 1990; Kennaway et al. 2002; Lewy et al. 1980). As an important chronobiotic regulator controlled by SCN, melatonin is mainly synthesized in the pineal gland. Once produced, it will not be stored but released into circulation immediately. In the liver, melatonin is rapidly metabolized into 6-hydroxymelatonin with a half-life of 20 ~ 30 min. Therefore, the circulating melatonin level can accurately reflect the melatonin synthesis rate in pineal gland (Claustrat et al. 2005b; Pevet et al. 2017). In this case, we investigated the effect of cutaneous irradiation on plasma melatonin levels, which indicated whether cutaneous exposure can affect the central clock in a short time.
Advances in the pharmacological management of non-24-h sleep-wake disorder
Published in Expert Opinion on Pharmacotherapy, 2021
Shohei Nishimon, Naoya Nishino, Seiji Nishino
Melatonin is detected not only in biological fluids such as the cerebrospinal fluid, saliva, breast milk, amnion liquid, bile, and synovial fluid, but also in extrapineal tissues, including the brain, retina, lens, Harderian gland, cochlea, thymus, thyroid, respiratory epithelium, gastrointestinal tract, kidney, liver, pancreas, spleen, endothelial cells, immune cells, and skin [68]. Melatonin levels in biological fluids are higher than those in the blood [68]. Melatonin is immediately metabolized in the liver or skin, but there are distinct differences in the route of delivery between oral and transdermal administration [55,69–71]. Orally administrated melatonin is metabolized to 6-hydroxymelatonin by cytochrome P450 (CYP450) in the liver. Meanwhile, melatonin administered transdermally displays a slower absorption rate with possible deposition in the skin, and has been shown to exhibit a protective effect against ultraviolet radiation (UVR)-induced skin damage and mitochondrial dysfunction [72–74].
Tasimelteon for treating non-24-h sleep-wake rhythm disorder
Published in Expert Opinion on Pharmacotherapy, 2019
Shohei Nishimon, Mari Nishimon, Seiji Nishino
Melatonin is also detected in biological fluids and extrapineal tissues, including brain, lens, retina, Harderian gland, cochlea, thyroid, thymus, respiratory epithelium, liver, kidney, pancreas, spleen, gastrointestinal tract, immune cells, endothelial cells, and skin [47]. Melatonin levels in biological fluids, such as cerebrospinal fluid, saliva, amnion fluid, maternal milk, synovial fluid, and bile, are higher than those in the blood [47]. Although melatonin is rapidly metabolized in the liver or peripheral tissues, such as skin [48–50], there is a distinct difference in the route of delivery between orally- and transdermally administered melatonin [51]. Orally administered melatonin is metabolized in the liver into 6-hydroxymelatonin by cytochrome P450 (CYP450). Transdermally administered melatonin indicates slow absorption and deposition in the skin [52] and has protective effects against ultraviolet radiation (UVR)-induced skin damage and mitochondrial dysfunction [53,54].