Melatonin is a ubiquitous molecule Essay Example

Melatonin is a ubiquitous molecule Essay Introduction Melatonin ( N-acetyl-5-methoxytryptamine ) is a omnipresent molecule, synthesised chiefly in the pineal secretory organ, secondary beginnings are in the retina, the GI piece of land, tegument, bone marrow and lymphocytes.1 It was foremost characterised after its isolation from bovid pineal secretory organs and structurally identified in 1958 by Lerner et al.2 The construction of melatonin ( Fig. 1 ) explains its diverseness with respects to its maps. The two functional groups define the molecule s amphiphilitic nature and specificity of receptor binding.3 Due to melatonin being both lipid and H2O soluble, it is non confined to one cellular compartment. Exogenously added melatonin can readily go through through the blood-brain barrier and be easy distributed to all subcellular compartments, which makes this molecule really versatile.4 We will write a custom essay sample on Melatonin is a ubiquitous molecule specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Melatonin is a ubiquitous molecule specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Melatonin is a ubiquitous molecule specifically for you FOR ONLY $16.38 $13.9/page Hire Writer Melatonin has assorted maps ; it is of import as an index of clip and day of the month and is considered to be the organic structure s chronological pacemaker.1 It is besides known to be a really effectual antioxidant, has immune-enhancing belongingss, is cytoprotective, has anti-apoptotic signalling map every bit good as oncostatic properties.1 The engagement of melatonin in such a wide scope of critical maps in the organic structure makes it pharmacologically a really interesting compound, but melatonin is sold as a nutrient addendum and is non-patentable harmonizing to the US FDA as a consequence. Therefore melatonergic agonists or melatonin parallels that are patentable are of greater involvement to the pharmacological industry.5 Pharmacological and/or biological activity Overview In pinealocytes ( cells of the pineal secretory organ ) tryptophan is converted to serotonin via 5-hydroxytryptophan after which it is acetylated to organize N-acetylserotonin by arylakylamine N-acetyltransferase ( AA-NAT ) . By the action of Hydroxyindole-O-methyltransferase ( HIOMT ) N-Acetylserotonin can be converted to melatonin.1 Alternatively, melatonin can be formed by N-acetylation of 5-methoxytryptamine. In most articles AA-NAT is said to be the rate-limiting enzyme3,7,8, but it is suggested that HIOMT might be a rate restricting enzyme in some cases6. Melatonin biogenesis is mostly regulated by the light/dark rhythm via the suprachiasmatic karyon ( SCN ) in the hypothalamus. Specialized nerve cells in the eyes respond to visible radiation and reassign the message to the SCN. The message is transduced in a roundabout tract to the pineal secretory organ. Melatonin synthesis is triggered by darkness. Norepinephrine is secreted during nighttime and twosomes to beta-adrenergic receptors. This consequences in camp formation and finally stimulation of arylalkylamine-N-acetyltransferase ( AA-NAT ) .7 Extrapineal melatonin is non regulated by circadian beat, nevertheless and it is hypothesised that it is produced as a agency of protection in response to certain stressors, eg. Ultraviolet radiation, pollutants, infections etc. that may ensue in oxidative emphasis or inflammation.6 Go arounding melatonin is chiefly metabolised by cytochrome P450 enzymes, CYP1A2, CYP1A1 and CYP2C19 in the liver or CYP1B1 at extrahepatic sites.6 Resulting 6-hydroxymelatonin by CYP1A, CYP1A2 or CYP1B1 can be conjugated with sulphate ( and glucoronide to a lesser extent ) to organize a more hydrophilic compound, 6-sulfatoxymelatonin ( aMT6S ) , which can be excreted in piss by the kidney.1 CYP2C19 or CYP1A2 are cytochromes involved in the demethylation of melatonin to N-acetylserotonin. 6-Hydroxymelatonin is non merely formed through enzymatic agencies as stated above, but besides through the interaction of melatonin with reactive O species ( ROS ) and reactive N species ( RNS ) .6 Melatonin has the ability to neutralize free groups, ROS and RNS every bit good as stimulate antioxidative enzymes such as superoxide dismutase ( SOD ) , catalase ( CAT ) , glutathione peroxidase ( GSH-Px ) and glutathione reductase ( GSH-Rd ) .4,9 Other metabolites of melatonin include 2-hydroxymelatonin, which is postulated to be a merchandise of melatonin s reaction with ROS/RNS,6 every bit good as cyclic 3-hydroxymelatonin ( C3-OHM ) , N1-acetyl-N2-formyl-5-methoxykynuramine ( AFMK ) and N-acetyl-5-methoxykynuramine ( AMK ) . The parent endocrine, melatonin, and its metabolites are of import in protecting cells from harm by free groups and reactive O and reactive N species. Melatonin metamorphosis by cytochrome P450 enzymes Pineal melatonin is metabolized to 6-hydroxymelatonin chiefly and it was found that CYP1A1, CYP1A2, CYP1B1 and CYP2C19 are the enzymes responsible for the production of this metabolite.1,6,10 Melatonin can besides be converted into N-acetylserotonin which is besides a precursor for its synthesis ( fig.1 ) 1. Both 6-hydroxymelatonin and N-acetylserotonin can be excreted in the piss after junction with sulfate and/or glucoronide. A survey conducted by Facciola et Al. ( 2001 ) 11 determined CYP1A2 to be the chief cytochrome P450 enzyme responsible for 6-hydroxylation of melatonin. In a survey that was conducted by Ma et Al. ( 2005 ) 10, melatonin 6-hydroxylation and O-demethylation rates were measured to measure the possible function of 11 cDNA-expressed human cytochrome P450 enzymes in melatonin metamorphosis ( figure 2 ) 10. It was found that 6-hydroxylation was chiefly carried out by CYP1A2, CYP1A1 and CYP1B1 and to a lesser extent CYP2C19 ( fig.2 A ) wherease O-demethylation occurred about chiefly due to the action of CYP2C19 and to a minimal grade by CYP1A2 ( fig.2 B ) . Inhibitory action of melatonin on human cytochrome P450 enzymes CYP1A1, CYP1A2 and CYP1B1 In a recent survey by Chang et Al. ( 2010 ) 12 the hypothesis that melatonin inhibits catalytic activity of CYP1A1, CYP1A2 and CYP1B1 along with CYP2A6 was tested, along with its consequence on the change of human CYP1 cistron look and on the activity of the human aryl hydrocarbon receptor ( AhR ) . A important consequence could turn out utile during malignant neoplastic disease therapy since these enzymes were found to be procarcinogen-bioactivating enzymes of benzo [ a ] pyrene or 7,12-dimethyl-benz [ a ] anthracene. Inhibition of look or decrease in catalytic activity of these cytochrome P450 isozymes may cut down the production of carcinogenic metabolites from these substrates. As described in the old subdivision, melatonin is metabolised by CYPs 1A1, 1A2 and 1B1. Therefore, its repressive consequence may be due to it viing with the procarcinogenic substrate for the enzymes active sites, although the exact mechanism of suppression is ill-defined. The survey mentioned that endogenous melatonin does non exercise repressive effects and resultingly a pharmacological potency in developing parallels of melatonin that could potentially suppress these enzymes and prevent CYP1 mediated carcinogenesis is created.12 Activity of melatonin with AhR and melatonin s consequence on CYP1 cistron look was found to be undistinguished. Fluvoxamine and melatonin Fluvoxamine ( FLU ) , an antidepressant, was found to increase serum melatonin degrees and a survey was conducted by von Bahr et Al. ( 2000 ) 13 to find whether citalopram ( CIT ) besides affects these degrees. The article concluded that CIT in fact does non hold the same consequence as FLU does. It did nevertheless set up a clear relationship between the degrees of melatonin and concentrations of FLU in the plasma of the subjects.13 FLU is an inhibitor of CYP1A2 and CYP2C19 and thereby prevents these enzymes from metabolizing melatonin into its metabolites ; resultantly an addition in the degrees of serum melatonin was witnessed. Melatonin as a free extremist scavenger and antioxidant Melatonin and its metabolites have the possible to move as free extremist scavengers and can neutralize reactive O species ( ROS ) and reactive N species ( RNS ) every bit good as up-regulate antioxidative enzymes, superoxide dismutase ( SOD ) , catalase ( CAT ) , glutathione peroxidase ( GSH-Px ) and glutathione reductase ( GSH-Rd ) .4 The free extremist dioxide ( O2- ) can be generated due to cellular respiration, due to environmental factors or oxidative explosion of macrophages. The toxicity of the O2- is considered to be low 9 but if it reacts with azotic oxide ( NO†¢ ) it can bring forth ONOO- capable of making molecular harm. SOD converts dioxide to hydrogen peroxide ( H2O2 ) which is non genuinely a free group, but if non catabolised to organize H2O and O2 via CAT or to H2O via GSH-Px, can be metabolised to the highly toxic hydroxyl extremist ( †¢OH ) . As can be seen in the figure, this free group can bring on DNA harm, lipid peroxidation or make harm to proteins. Melatonin can be converted into a metabolite cyclic 3-hydroxymelatonin when it reacts with two hydroxyl groups, which has been found to be excreted in the urine.1,9 An AFMK tract ( figure 5 ) 1 besides exists that is evident capable of scavenging up to 10 ROS/RNS.6 AFMK and AMK are powerful free extremist scavengers and defenders against oxidative emphasis, but besides has anti-inflammatory and immunoregulatory effects by suppressing tumour mortification factor-alpha ( TNFa ) and interleukin-8 formation ( IL-8 ) and synthesis of prostaglandins.6 The chief metabolite of melatonin, 6-hydroxymelatonin, can besides be generated in melatonin s reaction with ROS/RNS, every bit good as another melatonin metabolite, 2-hydroxymelatonin.6 Melatonin and its chronobiotic effects Melatonin is a major regulator of the circadian beat and acts via the suprachiasmatic karyon ( SCN ) in the hypothalamus. Melatonin acts through MT1 and MT2 receptors in the SCN and MT1 is associated with repressive effects of electrical activity in SCN nerve cells, whereas melatonin s actions on MT2 are involved with the ordinance of the circadian rhythm.5 Melatonin synthesis extremums during the dark stage and is inhibited by visible radiation. Exogenous melatonin disposal at certain clip periods consequences in displacements in the circadian beat. It is hence considered to be utile in the intervention of jet slowdown and in publicity of reposeful slumber, although melatonin is likely non a direct hypnotic.7 Decision Melatonin is a compound with so many diverse maps in the organic structure, for illustration its regulative function in circadian beat, antioxidant and oncostatic belongingss. This compound is of pharmacological significance, but is besides sold amp ; lsquo ; over the counter A ; rsquo ; as a nutrient addendum and is resultantly non patentable. This restricts pharmacological involvement to a certain extent, although the development of melatonin parallels that are more efficient in its capableness to exercise these maps, for illustration increased half life with retension of consequence, may be of important value for research workers and the pharmaceutical industry. Melatonin is besides involved in the protection against neurodegenerative diseases, depression and immune map. There is no uncertainty as to how of import melatonin is with respects to physiological operation is in populating beings. It is critical for our perceptual experience of clip and day of the month and is protects us from risky environmental agents every bit good as from ourselves ( eg, the free groups produced via natural O metamorphosis with which we can non be without ) . More research into the mechanisms by which melatonin exerts its antioxidant effects and how extrapineal melatonin can be induced or inhibited every bit good as drug-drug interactions would be of great benefit when developing curative schemes in the combat of diseases, such as Alzheimer s Disease, Parkinson s Disease, insomnia, diseases of the immune system, malignant neoplastic disease and many more. Mentions Pandi-Perumal et Al. Melatonin: Nature s most various biological signal Lerner A.B. , Case J.D. , Takahashi Y ( 1958 ) Isolation of melatonin, a pineal factor that lightens melanocytes. J.Am.Chem.Soc. 80: 2587 Hardeland R. , Pandi-Perumal S.R. , Cardinali D.P. ( 2006 ) Molecules in focal point: Melatonin. The International Journal of Biochemistry A ; Cell Biology 38: 313-316 Reiter R.J. ( 1995 ) Oxidative Procedures and Antioxidative defence mechanisms in the aging encephalon. FASEB J. 9: 526-533 Pandi-Perumal S.R. , Srinivasan V. , Poeggeler B. , Hardeland R. ( 2007 ) Drug penetration: usage of melatonergic agonists for intervention of insomnia focal point on ramelteon. Nature Clinical Practice Tan et. Al ( 2007 ) One molecule, many derived functions: A ceaseless interaction of melatonin with reactive O and N species Reiter R.J. ( 2003 ) Melatonin: clinical relevancy Best Practice A ; Research Clinical Endocrinology and Metabolism Vol. 17, No.2. pp. 273-285 Claustrat et. Al ( 2005 ) The basic physiology and pathophysiology of melatonin Sleep Medicine Reviews 9: 11-24 Reiter R.J. et Al ( 2000 ) Actions of Melatonin in the Reduction of Oxidative Stress. J.Biomed.Sci 7: 444-458 Ma. et Al ( 2005 ) Metamorphosis of melatonin by human cytochromes P450 DMD 33: 489-494 Facciola et. Al ( 2001 ) Cytochrome P450 isoforms involved in melatonin metamorphosis in humanliver microsomes Eur J Clin Pharmacol 56: 881-888 Chang et Al. ( 2010 ) Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin J. Pineal Res. 48: 55-64 von Bahr et Al. ( 2000 ) Fluvoxamine but non citalopram additions serum melatonin in healthy topics an indicant that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin