Melatonin: Deacetylation to 5‐methoxytryptamine by Liver but Not Brain Aryl Acylamidase

Rogawski, Michael A.; Roth, Robert H.; Aghajanian, George K.

doi:10.1111/j.1471-4159.1979.tb11049.x

Cited by 59 publications

(47 citation statements)

References 35 publications

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“…It has remained uncertain to what extent non-specific AAAs of vertebrate origin are capable of deacetylating melatonin at all. 5-MT formation from melatonin was reported for mammalian liver, whereas, in the same studies, no such conversion was observed in the brain [9,112].…”

Section: Melatonin Deacetylationmentioning

confidence: 72%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

110

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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Section: Melatonin Deacetylationmentioning

confidence: 72%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

110

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“…However, the melatonin-induced increase in the tissue level of serotonin can be seen in all of the brain structures studied of pargyline-treated rats with a partial lesion of the serotonergic system. Under these experimental conditions, the physiologic synthesis and storage of serotonin is diminished by the neurotoxin 5,7-DHT specific to the serotonergic system, and the amount of serotonin formed by an alternative pathway (via 5-MT O-demethylation by CYP2D) is raised due to a supply of an exogenous substrate (i.e., 5-MT formed from exogenous melatonin in the liver) (Rogawski et al, 1979;Beck and Jonsson, 1981), which crosses the blood-brain barrier (Acuña-Castroviejo et al, 2014). Moreover, both peripheral and brain 5-MT and serotonin formed from it are protected by intraperitoneal pargyline against MAO oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…Being an amphiphilic substance, peripheral melatonin easily crosses the blood-brain barrier (Green et al, 1975). Circulating melatonin is metabolized mainly in the liver by cytochrome P450 isoforms of the CYP1A subfamily (CYP1A1/A2/B1) to form 6-hydroxymelatonin and then 6-sulfatoxymelatonin (Ma et al, 2005;Hardeland, 2010), but it can also be deacetylated to 5-methoxytryptamine (5-MT) (Rogawski et al, 1979;Beck and Jonsson, 1981).…”

Section: Introductionmentioning

confidence: 99%

“…Intraperitoneal pargyline was applied to prevent 5-MT (successively formed from melatonin in the liver) and serotonin (formed from 5-MT in the brain) from the oxidation by MAO and thus to potentiate the effect of melatonin on the serotonin level in the brain (Prozialek and Vogel, 1978;Suzuki et al, 1981;Galzin and Langer, 1986;Raynaud and Pévet, 1991). Intracerebral 5,7-DHT (a neurotoxin specific to serotonergic neurons) was used to decrease the production of serotonin via a classic pathway from tryptophan and serotonin storage in neuronal terminals of the brain (Rogawski et al, 1979;Beck and Jonsson, 1981) and, consequently, to enhance serotonin derived from the peripherally formed 5-MT (from melatonin), as well as to demonstrate the role of cytochrome P450 present in neurons/terminals in serotonin formation from 5-MT via an alternative pathway. The extracellular, functional concentration of serotonin in the striatum (involved in motor functions) was measured in the absence/ presence of pargyline using an in vivo microdialysis (model B).…”

Section: Introductionmentioning

confidence: 99%

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Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain

Haduch

Bromek

Wójcikowski

et al. 2016

Drug Metabolism and Disposition

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Melatonin is used in the therapy of sleep and mood disorders and as a neuroprotective agent. The aim of our study was to demonstrate that melatonin supported (via its deacetylation to 5-methoxytryptamine) CYP2D-mediated synthesis of serotonin from 5-methoxytryptamine. We measured serotonin tissue content in some brain regions (the cortex, hippocampus, nucleus accumbens, striatum, thalamus, hypothalamus, brain stem, medulla oblongata, and cerebellum) (model A), as well as its extracellular concentration in the striatum using an in vivo microdialysis (model B) after melatonin injection (100 mg/kg i.p.) to male Wistar rats. Melatonin increased the tissue concentration of serotonin in the brain structures studied of naïve, sham-operated, or serotonergic neurotoxin (5,7-dihydroxytryptamine)-lesioned rats (model A). Intracerebroventricular quinine (a CYP2D inhibitor) prevented the melatonin-induced increase in serotonin concentration. In the presence of pargyline (a monoaminoxidase inhibitor), the effect of melatonin was not visible in the majority of the brain structures studied but could be seen in all of them in 5,7-dihydroxytryptamine-lesioned animals when serotonin storage and synthesis via a classic tryptophan pathway was diminished. Melatonin alone did not significantly increase extracellular serotonin concentration in the striatum of naïve rats but raised its content in pargyline-pretreated animals (model B). The CYP2D inhibitor propafenone given intrastructurally prevented the melatonin-induced increase in striatal serotonin in those animals. The obtained results indicate that melatonin supports CYP2D-catalyzed serotonin synthesis from 5-methoxytryptamine in the brain in vivo, which closes the serotonin-melatonin-serotonin biochemical cycle. The metabolism of exogenous melatonin to the neurotransmitter serotonin may be regarded as a newly recognized additional component of its pharmacological action.

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“…Melatonin is also metabolized in the brain by indole-2,3-dioxygenase to give rise to N-acetyl-N'-formyl-5-methoxykynurenamine (Hirata et al 1974). Other minor metabolic 0004-9417/86/040427$02.00 pathways include demethylation to N-acetyl-5-hydroxytryptamine (Leone and Silman 1984) and deacetylation to 5-methoxytryptamine (Rogawski et al 1979).…”

Section: Introductionmentioning

confidence: 99%

Prolactin Response in Border-Leicester X Merino Ewes to Administration of Melatonin, Melatonin Analogues, a Melatonin Metabolite and 6-Methoxybenzoxazolinone

Kennaway¹,

Royles²,

Dunstan³

et al. 1986

Aust. Jnl. Of Bio. Sci.

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The effect of structural modifications of the melatonin molecule on plasma half-life of the analogues and basal prolactin secretion was studied in Border-Leicester x Merino ewes. Halogenation at position 6 and/or unsaturation of the 2,3-double bond of the melatonin molecule slightly lengthened the halflife of the analogues. Melatonin, 6-chloromelatonin, 2,3-dihydromelatonin and 6-chloro-2,3-dihydromelatonin decreased plasma prolactin to 31, 45, 54 and 48% of control levels respectively when administered daily (100 p.g at 1600 h) for 21 days. The brain metabolite of melatonin, N-acetyl-N'-formyl-5-methoxykynurenamine, and the putative natural melatonin analogue, 6-methoxybenzoxazolinone, failed to affect prolactin levels when administered in a similar manner. These results indicate that certain structural modifications to the melatonin molecule can be tolerated biologically; however, the modifications reported here still did not prevent rapid clearance from the circulation.

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Melatonin: Deacetylation to 5‐methoxytryptamine by Liver but Not Brain Aryl Acylamidase

Cited by 59 publications

References 35 publications

Melatonin Metabolism in the Central Nervous System

Melatonin Metabolism in the Central Nervous System

Melatonin Supports CYP2D-Mediated Serotonin Synthesis in the Brain

Prolactin Response in Border-Leicester X Merino Ewes to Administration of Melatonin, Melatonin Analogues, a Melatonin Metabolite and 6-Methoxybenzoxazolinone

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