H2 ii ccncch

Figur« 8.HM Melatonin synthesis in the pineal gland found to vary between indiv iduals by more than an order of magnitude (Waidliauser et aL 1984).

Transport and cellular uptake

Blood circulation: Only very small amounts of melatonin, normally around 7ng/l (Ludemann ftal., 2(H)!). arc circulating with blood. The melatonin precursor 5-HT is taken up into pinealocytes by a specitie sodium- and chloride-dependent transporter (SLC6A4). The importance of transporter-mediated uptake to prov ide the precursor for melatonin synthesis is suggested by the frequent occurrence of a less active form in patients with seasonal-affective disorder (Partonen and Lonnqvist. I99X}

Metabolism

The main melatonin metabolite is 6-hydroxymclatonin: smaller amounts are broken down into the serotonin metabolites 5-OH-indole 3-acctate and N1 -acetyl-N2-formyl-

5-mcthoxykynuramine.

Melatonin is hydroxy luted at position 6 by CYPIA2 (EO.14.14.1) and other cytochromes in the liver (Facciola ft al.. 2001). Conjugation by 3'-phosphoadcnosuie 5'-phosphosullate< PA PS i-dependent sulfotransfcrase ST1A3 (EC2.8.2.3} then generates

6-sulfatoxymelatonin (6-SMT). the main melatonin metabolite (Honma ft at., 2001). Ring opening of melatonin anil generation of N1-acetyl-N2-formyI-5-methoxy-

kynuramine occurs either through enzyme action or by reaction with oxygen free radicals. The hemoproteins indoleamine-pyrrole 2,3-dioxvgcnase (ECl.l3.lt.42) and peroxidase (myeloperoxidase. EC1.11.1.7) generate Nl-acetyl-N2-formy)-5-methoxy-kynuramine (Tan et a!., 2001), The same intermediate appears to be formed non-enzytnieally when melatonin reacts with various oxygen free radicals.

Melatonin can Ik* metabolized to 5-OH-indole 3-acetate in the liver, presumably via serotonin. N-acetylserotonin may be generated (Beedham et a!., 19X7) by a reversal of the reaction catalyzed by the melatonin-synthesis enzyme acctylscrotonin O-methyltransferase (EC2.1.1.4). Aryl-aeylamidase (EC3.5.1.13) deaeetylates melatonin (Rogawski et al., 1979).

Most 5-HT is metabolized by amine oxidase (monoamine oxidase A, MAO-A: EC! .4.3.4. FAD-containing) and one or more of the aldehyde dehydrogenases (A ID11: EC 1,2.1,3/NAD-rcquiring, F.CI.2.1,47MADP-requiring. EC1.2.I.5/NAD or NADP-requiring) to 5-hydrnxyindole-3-acetate. Smaller amounts of 5-HT enter the main tryptophan calabolic pathway through the action of tryptophan 2,3-dioxygenase (ECl.13.ll.il). Alcohol dehydrogenase (EC1.1,1.1) convens some 5-HT into the dead-end product 5-hydroxytryptophol (5-HTOl ). Ethanol acutely increases conversion of 5-HT into 5-HTOL (Helander and Some. 2000).

Storage

The dense core granules of pinealocytes contain melatonin; storage and release is mediated by vesicular monoamine transporters.

N1 -Aratyl-N2-fo™y!-5-n>etlw,<yi<y nur amino

Indoleamin-pyrrols 2.3-dio<y5(enase

II ctV0

6-Hydroxymeratonm

II ctV0

N-Acetylsetolonm

Aryt-acytamtfase

6-Hydroxymeratonm

Suite--transieras« ST1 A3

¿iílflnnsjnrt-r, 5 tnsprtoapíijiw?

5-OH Ttyptomine (Sttioíoninl

Amine onioase (FAD)

6- Suit aKHtynwiatonin

5-H^ci/oíyindole aidetiyds

A;dehyrte aenydrorfenase f NADiP) + H .0 ^ NAD(P)H

5-Hydronyindole acetate

5-Hydronyindole acetate

Figure B.tOS Melatonin cata bo I ism

Excretion

The main products of melatonin metabolism in urine arc 6-SMT and 5-hydroxy -indole 3-acctalc. 6-SMT excretion is about 0.4 p.gkg body weight, slightly higher in winter than in summer (Davis et at.. 2001). Supplemental intake of 5mg melatonin was found to double 6SM1 excretion (Pierard et at., 2001).

Regulation

The activity of the 5-HT transporter that ferries the melatonin precursor into pinealocytes is tightly controlled. 5-1 IT-uptake and melatonin synthesis increase in the absence of light exposure (Lima and Schmeer, 1994).

Function

Receptor binding: Melatonin binds to and activates specific G-protein-coupled membrane receptors. Nearly 20 genes have been identified thai code for putative melatonin receptors, including mt I. MT2. and Mellc. Expression of mtl is particularly high in neurons of the supraehiasmatic nucleus and the pars tuberalis of the pituitary. Orcadian rhythm. During the dark periods of the daily cycle the supraehiasmatic nucleus stimulates expression of the arylalkvlamine N gene and thereby increases production and secretion of melatonin at night. Ocular light exposure, but not extraocular illumination, shifts eircadian rhythms and suppresses nocturnal melatonin production {Lock ley et a!.. 1998: Hebcrt el a/., 1999). The efficacy of oral melatonin supplements for the relief of jet-lag remains in doubt tSpit/er el til., 1999). Seasonal rhythm: The modulation of melatonin rhythm by light exposure appears to entrain seasonal temporal organization iPevet, 2000), The investigation of seasonally recurring events influenced by melatonin cycles has (bcussed mainly on estrus of horses and other mammals, and on the behavior of songbirds. The relevance for human performance or health remains unknown.

Influences on mood: Melatonin may have anxiolytic properties. Preoperative use of 0.05 mg'kg reduced anxiety and relaxation without impairing cognitive and psychomotor skills (Naguib and Samarkand!, 2000).

Abnormal attenuation of the nocturnal rise in plasma melatonin may be related to night-eating syndrome (NES), which consists of morning anorexia, evening hyper-phagia. and insomnia (Birketvedt et aL 1999).

Skin pigmentation Uptake of melatonin increases pigment production of melanocytes and stimulates their cell division (Iyengar. 2000).

Free radical scavenging: Protectiv e effects against oxidative DNA damage and thereby antitumorigenic properties have been observed in some animal studies tKarbownik etui.. 2000). It has been suggested that at sub-micrumolar concentrations melatonin is 50 70 times more effective as an antioxidant compared to ascorbate or alpha-tocopherol. T his high potency might be related to its ability to scavenge hydroxy! radicals directly and thereby terminate fenton-type reactions (Qi el aL, 2000). The metabolite N l-aeetyl-N2-formyl-5-methoxykynuramine may be an even more potent antioxidant than melatonin itself (Tan et at., 2001).

Immune function: Circulating melatonin may be an important element of neuroim-mune communication that periodically stimulates immune response. Cytokine (e.g. 11.-6) production in lymphocytic and monocytic cells is stimulated through binding of melatonin lo nuclear receptors (Guerrero et at.. 20(10). The pineal gland may exert oncostatic actions on distant tissues, and melatonin has been suggested to aid in the suppresion of tumor proliferation (Cos and Sanchez-Barcelo. 2000). Hormonal fimction: There have been reports that growth hormone secretion is influenced by melatonin at a hypothalamic level (Meeking et a!.. 1490).

Melatonin reduces the sensitivity of the thyroid to thyrotropin (TSII), inhibits thyroid cell proliferation, and lowers thyroxine secretion.

Fertility Sperm cell maturation is promoted through a stimulating effect of melatonin on eptdidymal cells.

References

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Beedham C, Smith JA, Steele DL, Wright PA. Chlorproma/ine inhibition of melatonin metabolism by normal and induced rat liver microsomes Eur J Drug Metah Pharmacokin 1987:12:299-302 Hirketvedt (iS, Florliolmen J. Sundsfjord J. Osterud B, Dinges D. Bilker W. Stunkard A. Behavioral and neuroendocrine characteristics of the night-eating syndrome. JAMA 1999:282:657-63

Cos S. Sanchez-Barcelo EJ. Melatonin, experimental basis for a possible application in breast cancer prevention and treatment, tiistol Histopathol 2000:15:637-47 Davis S, kaune W I. Mirick Dk. Chen (.. Stevens RC. Residential magnetic liclds. light-at-mghi, and nocturnal urinary h-sulfatoxymelatonin concentration in women. Am J Epidemiol 2001: i 54:591 -6(H) Facciola G. I lidestrand M. von Balir C. Tybring G. Cytochrome P45t) isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol 2001:56:881 8

Guerrero JM. Pozo D. Garcia-Mauri no S. Carrillo A, Osuna C. Molinem P, Calvo JR. Nuclear receptors are involved in the enhanced IL-6 production by melatonin in U937 cells. Biol Signals Receptors 2000:9:197 202 Hebert M. Martin Sk, Eastman CI. Nocturnal melatonin secretion is not suppressed by light exposure behind the knee in humans. Neurosci Lull 1999;274:127 30 Helandcr A, Some M. Dietary serotonin and alcohol combined may provoke adverse physiological sv inptoms due to 5-hydmxytrvptophoI, Life Set 2000:67:799 806 Honma W. kamiyama Y. Yoshinari k. Sasano II. Shimada M. Nagata K. Yamazoe Y, Enzymatic characterization and interspecies difference of phenol sulfoiransferases. ST1A forms. Drug Metah Disp 2001:29:274- 81 Iyengar IV Melatonin and melanocyte functions. Biol Signals Receptors 2000;9:260-6

Karbownik M, Tan DX, Reiter RJ Melatonin reduces the oxidation of nuclear DNA and membrane lipids induced by the carcinogen delta-aminolevulinic acid, hit J Cancer 21)00:88:7 II

Klarsko\ k. Johnson kL, Benson LM. Cileich CiJ. Naylor S. Eosinophilia-myalgia syndrome case-associated contaminants in commercially available 5-!iydroxytryptophan. Adv Exp Med Biol 199<i;467:461-8 Laforce R. Rigoz/t k. Paganetti M, Mossi W. Cuainazzi P. Calderari G. Aspects of melatonin manufacturing and requirements for a reliable active component. Biol Signals Receptors 1909:8:143 6 Lima L. Schtneer C. Characterization of serotonin transporter in goldfish retina by the binding of [3H]paroxetine and the uptake of [3FJ| serotonin: modulation by light. JNeumchem 1994:62:528-35 Lock ley SW, Skene DJ, Thapan K, English J. Ribeiro D, Haimov L Hampton S. Middleton B, von Sehantz M. Arendt J, Extraocular light exposure does not suppress plasma melatonin in humans. J Clin Endocrinol Metab 1998;83:3369-72 Ludemann P. Xwernemann S. Lerchl A, Clearance of melatonin and 6-suIfatoxynielatonin by hemodialysis in patients with end-stage renal disease. ./ Pineal Res 2001: 31:222-7

Meeking DR. Wallace JD. Cunco RC . Forsling M. Russell-Jones DL. Exercise-induced till secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects. Eur J Endocrinol 1999:141:22 6 Naguib M. Samarkand) AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000;91:473-9 Partonen T, Lonnqvist J. Seasonal affective disorder Lancet 1998:352:1369-74 Pevet P Melatonin and biological rhythms. Biol Signals Receptors 2000:9:203 12 Pierard C. Beaumont M. Ens I en M. ChaulVard F, Tan DX. Re iter RJ. I ontan A. French J, Coste O, Lagarde D. Resynehronizaiion of hormonal rhythms after an eastbound flight in humans: effects of slow-release caffeine and melatonin. EurJAppl Physiol 2001:85:144 50

Qi W. Re iter RJ. Tan DX. Garcia JJ. Manchester LC. karbownik M. Calvo JR. Chroniiumt 111 (-induced 8-hydroxydeoxyguanosinc in DNA and its reduction by antioxidants: comparative effects of melatonin, ascorbate, and vitamin E. Env Health Persp 2(H)0; 108:399 402 Rogawski MA, Roth RH, Aghajanian GK. Melatonin: deaeetylation to 5-methoxvtrypta-

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Understanding And Treating Autism

Understanding And Treating Autism

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