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Identification
Name Melatonin
Accession Number DB01065 (APRD00742, DB08189)
Type small molecule
Groups approved, nutraceutical
Description

Melatonin is a biogenic amine that is found in animals, plants and microbes. Aaron B. Lerner of Yale University is credited for naming the hormone and for defining its chemical structure in 1958. In mammals, melatonin is produced by the pineal gland. The pineal gland is small endocrine gland, about the size of a rice grain and shaped like a pine cone (hence the name), that is located in the center of the brain (rostro-dorsal to the superior colliculus) but outside the blood-brain barrier. The secretion of melatonin increases in darkness and decreases during exposure to light, thereby regulating the circadian rhythms of several biological functions, including the sleep-wake cycle. In particular, melatonin regulates the sleep-wake cycle by chemically causing drowsiness and lowering the body temperature. Melatonin is also implicated in the regulation of mood, learning and memory, immune activity, dreaming, fertility and reproduction. Melatonin is also an effective antioxidant. Most of the actions of melatonin are mediated through the binding and activation of melatonin receptors. Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis. Reduced melatonin production has also been proposed as a likely factor in the significantly higher cancer rates in night workers.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • MEL
  • MLT
  • N-acetyl-5-methoxytryptamine
  • Pineal Hormone
Brand names
  • Circadin (Lundbeck (France, United Kingdom), Neurim Pharmaceutical Labs (Israel, Denmark, Greece, Norway, Poland, Portugal), Nycomed (Belgium, Sweden))
  • Mela-T (Alacer Corp. (Canada))
  • Melatol (Elisium (Argentina))
  • Melatonex
  • Melatonin (Biomed International Products Corp., Nutravite Pharmaceuticals (2008) Inc., Viva Pharmaceutical Inc., Kripps Pharmacy Ltd., SunOpta Inc.)
  • Melatonine
  • Melovine
  • MT6
  • Nature'S Harmony (SunOpta Inc. (Canada))
  • Night Rest
  • Revital Melatonin (Chin Tai Ginseng Co., Ltd (Canada))
  • Rx Balance (SunOpta Inc. (Canada))
  • Sleep Right (SunOpta Inc. (Canada))
  • Vivitas (SunOpta Inc. (Canada))
Brand name mixtures
  • Plenovit Melatonina (melatonin + vitamin B6)
Categories
  • Antioxidants
  • Free Radical Scavengers
  • Anticonvulsants
  • Adjuvants, Immunologic
  • Central Nervous System Depressants
CAS number 73-31-4
Weight Average: 232.2783
Monoisotopic: 232.121177766
Chemical Formula C13H16N2O2
InChI Key InChIKey=DRLFMBDRBRZALE-UHFFFAOYSA-N
InChI
InChI=1S/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)
Plain Text
IUPAC Name
N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide
SMILES
COC1=CC2=C(NC=C2CCNC(C)=O)C=C1
Plain Text
Mass Spec show (8.2 KB)
Taxonomy
Kingdom Organic
Classes
  • Alkaloids and Alkaloid Derivatives
  • Tryptamines and Derivatives
Substructures
  • Indoles and Indole Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Pyrroles
  • Alkaloids and Alkaloid Derivatives
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Tryptamines and Derivatives
  • Phenyl Esters
Pharmacology
Indication Used orally for jet lag, insomnia, shift-work disorder, circadian rhythm disorders in the blind (evidence for efficacy), and benzodiazepine and nicotine withdrawal. Evidence indicates that melatonin is likely effective for treating circadian rhythm sleep disorders in blind children and adults. It has received FDA orphan drug status as an oral medication for this use. A number of studies have shown that melatonin may be effective for treating sleep-wake cycle disturbances in children and adolescents with mental retardation, autism, and other central nervous system disorders. It appears to decrease the time to fall asleep in children with developmental disabilities, such as cerebral palsy, autism, and mental retardation. It may also improve secondary insomnia associated with various sleep-wake cycle disturbances. Other possible uses for which there is some evidence for include: benzodiazepine withdrawal, cluster headache, delayed sleep phase syndrome (DSPS), primary insomnia, jet lag, nicotine withdrawal, preoperative anxiety and sedation, prostate cancer, solid tumors (when combined with IL-2 therapy in certain cancers), sunburn prevention (topical use), tardive dyskinesia, thrombocytopenia associated with cancer, chemotherapy and other disorders.
Pharmacodynamics Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions
Mechanism of action Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
Absorption The absorption and bioavailability of melatonin varies widely.
Volume of distribution Not Available
Protein binding n/a
Metabolism

Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 1B1 6-hydroxymelatonin 6-hydroxylation
Cytochrome P450 1A2 6-hydroxymelatonin 6-hydroxylation 6 0
Cytochrome P450 1A2 desmethylmelatonin O-demethylation
Cytochrome P450 1A1 6-hydroxymelatonin 6-hydroxylation
Route of elimination Not Available
Half life 35 to 50 minutes
Clearance Not Available
Toxicity

Generally well-tolerated when taken orally. The most common side effects, day-time drowsiness, headache and dizziness, appear to occur at the same frequency as with placebo. Other reported side effects include transient depressive symptoms, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion, nausea, vomiting, and hypotension. Safety in Adults: Evidence indicates that it is likely safe to use in oral and parenteral forms for up to two months when used appropriately. Some evidence indicates that it can be safely used orally for up to 9 months in some patients. It is also likely safe to use topically when used appropriately. Safety in Children: Melatonin appeared to be used safely in small numbers of children enrolled in short-term clinical trials. However, concerns regarding safety in children have arisen based on their developmental state. Compared to adults over 20 years of age, people under 20 produce high levels of melatonin. Melatonin levels are inversely related to gonadal development and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during Pregnancy: High doses of melatonin administered orally or parenterally may inhibit ovulation. Not advised for use in individuals who are pregnant or trying to become pregnant. Safety during Lactation: Not recommended as safety has not be established.

Oral, rat: LD50 ≥3200 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms Not Available
Prices
Unit description Cost Unit
Melatonin powder 45.6 USD g
Melatonin 3 mg tablet 0.22 USD tablet
Melatonin 5 mg tablet 0.12 USD tablet
Melatonin 5 mg tablet sl 0.1 USD tablet
Melatonin sublingual tablet 0.09 USD tablet
Melatonin 1 mg tablet 0.03 USD tablet
Patents Not Available
Properties
State solid
Melting point 117 oC
Experimental Properties
Property Value Source
logP 1.6 PhysProp
Predicted Properties
Property Value Source
water solubility 1.43e-01 g/l ALOGPS
logP 1.42 ALOGPS
logP 1.15 ChemAxon Molconvert
logS -3.21 ALOGPS
pKa 16.59 ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 54.12 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 66.28 ChemAxon Molconvert
polarizability 25.65 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Boutin JA, Audinot V, Ferry G, Delagrange P: Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 2005 Aug;26(8):412-9. Pubmed
  2. Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti EM: Melatonin in plants. Adv Exp Med Biol. 2003;527:593-7. Pubmed
  3. Hardeland R: Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005 Jul;27(2):119-30. Pubmed
  4. Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ: Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int. 1995 Mar;35(3):627-34. Pubmed
  5. Ma X, Chen C, Krausz KW, Idle JR, Gonzalez FJ: A metabolomic perspective of melatonin metabolism in the mouse. Endocrinology. 2008 Apr;149(4):1869-79. Epub 2008 Jan 10. Pubmed
  6. Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S: Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci. 2001 Jun;939:200-15. Pubmed
External Links
Resource Link
KEGG Compound C01598 Link_out
PubChem Compound 896 Link_out
PubChem Substance 46509101 Link_out
ChemSpider 872 Link_out
BindingDB 9019 Link_out
ChEBI 16796 Link_out
ChEMBL 16796 Link_out
Therapeutic Targets Database DAP000429 Link_out
HET ML1 Link_out
Drug Product Database 793167 Link_out
Drugs.com http://www.drugs.com/melatonin.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/mel_0286.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Melatonin Link_out
ATC Codes
  • N05CH01
  • N05CM17
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS show (72 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Melatonin receptor type 1A

Pharmacological action: yes
Actions: agonist

High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P48039 Link_out
Gene: MTNR1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Radogna F, Paternoster L, De Nicola M, Cerella C, Ammendola S, Bedini A, Tarzia G, Aquilano K, Ciriolo M, Ghibelli L: Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicol Appl Pharmacol. 2009 Aug 15;239(1):37-45. Epub 2009 May 19. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Boutin JA, Audinot V, Ferry G, Delagrange P: Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 2005 Aug;26(8):412-9. Pubmed
  4. Hardeland R: Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors. 2009 Mar-Apr;35(2):183-92. Pubmed
  5. Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP: Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. Adv Ther. 2010 Nov;27(11):796-813. Epub 2010 Sep 6. Pubmed
  6. Carocci A, Catalano A, Lovece A, Lentini G, Duranti A, Lucini V, Pannacci M, Scaglione F, Franchini C: Design, synthesis, and pharmacological effects of structurally simple ligands for MT and MT melatonin receptors. Bioorg Med Chem. 2010 Sep 1;18(17):6496-511. Epub 2010 Jul 3. Pubmed
  7. Prendergast BJ: MT1 melatonin receptors mediate somatic, behavioral, and reproductive neuroendocrine responses to photoperiod and melatonin in Siberian hamsters (Phodopus sungorus). Endocrinology. 2010 Feb;151(2):714-21. Epub 2009 Dec 4. Pubmed

2. Melatonin receptor type 1B

Pharmacological action: yes
Actions: agonist

High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P49286 Link_out
Gene: MTNR1B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Radogna F, Paternoster L, De Nicola M, Cerella C, Ammendola S, Bedini A, Tarzia G, Aquilano K, Ciriolo M, Ghibelli L: Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicol Appl Pharmacol. 2009 Aug 15;239(1):37-45. Epub 2009 May 19. Pubmed
  2. Boutin JA, Audinot V, Ferry G, Delagrange P: Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 2005 Aug;26(8):412-9. Pubmed
  3. Hardeland R: Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors. 2009 Mar-Apr;35(2):183-92. Pubmed
  4. Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP: Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. Adv Ther. 2010 Nov;27(11):796-813. Epub 2010 Sep 6. Pubmed
  5. Carocci A, Catalano A, Lovece A, Lentini G, Duranti A, Lucini V, Pannacci M, Scaglione F, Franchini C: Design, synthesis, and pharmacological effects of structurally simple ligands for MT and MT melatonin receptors. Bioorg Med Chem. 2010 Sep 1;18(17):6496-511. Epub 2010 Jul 3. Pubmed
  6. Prendergast BJ: MT1 melatonin receptors mediate somatic, behavioral, and reproductive neuroendocrine responses to photoperiod and melatonin in Siberian hamsters (Phodopus sungorus). Endocrinology. 2010 Feb;151(2):714-21. Epub 2009 Dec 4. Pubmed

3. Estrogen receptor

Pharmacological action: unknown
Actions: antagonist

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues

Organism class: human
UniProt ID: P03372 Link_out
Gene: ESR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. del Rio B, Garcia Pedrero JM, Martinez-Campa C, Zuazua P, Lazo PS, Ramos S: Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. 2004 Sep 10;279(37):38294-302. Epub 2004 Jun 30. Pubmed
  2. Yoo YM, Jeung EB: Melatonin-induced estrogen receptor alpha-mediated calbindin-D9k expression plays a role in H2O2-mediated cell death in rat pituitary GH3 cells. J Pineal Res. 2009 Nov;47(4):301-7. Epub 2009 Oct 1. Pubmed

4. Nuclear receptor ROR-beta

Pharmacological action: unknown
Actions: agonist

Orphan nuclear receptor required for normal postnatal development of rod and cone photoreceptor cells. Regulates transcription of OPN1SW in cone photoreceptor cells by binding the sequence 5'-AGGTCA-3' in the OPN1SW promoter (By similarity)

Organism class: human
UniProt ID: Q92753 Link_out
Gene: RORB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Becker-Andre M, Wiesenberg I, Schaeren-Wiemers N, Andre E, Missbach M, Saurat JH, Carlberg C: Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994 Nov 18;269(46):28531-4. Pubmed

5. Calmodulin

Pharmacological action: unknown

Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases

Organism class: human
UniProt ID: P62158 Link_out
Gene: CALM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. del Rio B, Garcia Pedrero JM, Martinez-Campa C, Zuazua P, Lazo PS, Ramos S: Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem. 2004 Sep 10;279(37):38294-302. Epub 2004 Jun 30. Pubmed
  2. Radogna F, Paternoster L, De Nicola M, Cerella C, Ammendola S, Bedini A, Tarzia G, Aquilano K, Ciriolo M, Ghibelli L: Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicol Appl Pharmacol. 2009 Aug 15;239(1):37-45. Epub 2009 May 19. Pubmed

6. Myeloperoxidase

Pharmacological action: unknown
Actions: inhibitor

Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity

Organism class: human
UniProt ID: P05164 Link_out
Gene: MPO Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Galijasevic S, Abdulhamid I, Abu-Soud HM: Melatonin is a potent inhibitor for myeloperoxidase. Biochemistry. 2008 Feb 26;47(8):2668-77. Epub 2008 Feb 1. Pubmed

7. Eosinophil peroxidase

Pharmacological action: unknown
Actions: inhibitor

Donor + H(2)O(2) = oxidized donor + 2 H(2)O

Organism class: human
UniProt ID: P11678 Link_out
Gene: EPX Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Lu T, Galijasevic S, Abdulhamid I, Abu-Soud HM: Analysis of the mechanism by which melatonin inhibits human eosinophil peroxidase. Br J Pharmacol. 2008 Jul;154(6):1308-17. Epub 2008 Jun 2. Pubmed

8. Calreticulin

Pharmacological action: unknown

Molecular calcium binding chaperone promoting folding, oligomeric assembly and quality control in the ER via the calreticulin/calnexin cycle. This lectin interacts transiently with almost all of the monoglucosylated glycoproteins that are synthesized in the ER. Interacts with the DNA-binding domain of NR3C1 and mediates its nuclear export

Organism class: human
UniProt ID: P27797 Link_out
Gene: CALR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hardeland R: Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors. 2009 Mar-Apr;35(2):183-92. Pubmed
  2. Macias M, Escames G, Leon J, Coto A, Sbihi Y, Osuna A, Acuna-Castroviejo D: Calreticulin-melatonin. An unexpected relationship. Eur J Biochem. 2003 Mar;270(5):832-40. Pubmed

9. Hydroxyindole O-methyltransferase

Pharmacological action: unknown

S-adenosyl-L-methionine + N-acetylserotonin = S-adenosyl-L-homocysteine + N-acetyl-5-methoxytryptamine

Organism class: human
UniProt ID: P46597 Link_out
Gene: ASMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Minneman KP, Wurtman RJ: The pharmacology of the pineal gland. Annu Rev Pharmacol Toxicol. 1976;16:33-51. Pubmed

10. Ribosyldihydronicotinamide dehydrogenase [quinone]

Pharmacological action: unknown

The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis

Organism class: human
UniProt ID: P16083 Link_out
Gene: NQO2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Radogna F, Paternoster L, De Nicola M, Cerella C, Ammendola S, Bedini A, Tarzia G, Aquilano K, Ciriolo M, Ghibelli L: Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicol Appl Pharmacol. 2009 Aug 15;239(1):37-45. Epub 2009 May 19. Pubmed
Enzymes

1. Cytochrome P450 1A1

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chang TK, Chen J, Yang G, Yeung EY: Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. J Pineal Res. 2010 Jan;48(1):55-64. Epub 2009 Nov 16. Pubmed
  2. Ma X, Idle JR, Krausz KW, Gonzalez FJ: Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489-94. Epub 2004 Dec 22. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 1A2

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chang TK, Chen J, Yang G, Yeung EY: Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. J Pineal Res. 2010 Jan;48(1):55-64. Epub 2009 Nov 16. Pubmed
  2. Ma X, Idle JR, Krausz KW, Gonzalez FJ: Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489-94. Epub 2004 Dec 22. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  4. Turpeinen M, Uusitalo J, Jalonen J, Pelkonen O: Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay. Eur J Pharm Sci. 2005 Jan;24(1):123-32. Pubmed

3. Cytochrome P450 1B1

Actions: substrate, inhibitor

Participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development

UniProt ID: Q16678 Link_out
Gene: CYP1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chang TK, Chen J, Yang G, Yeung EY: Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. J Pineal Res. 2010 Jan;48(1):55-64. Epub 2009 Nov 16. Pubmed
  2. Ma X, Idle JR, Krausz KW, Gonzalez FJ: Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489-94. Epub 2004 Dec 22. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Huuhka K, Riutta A, Haataja R, Ylitalo P, Leinonen E: The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study. Methods Find Exp Clin Pharmacol. 2006 Sep;28(7):447-50. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mo SL, Zhou ZW, Yang LP, Wei MQ, Zhou SF: New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126. Pubmed

6. Hydroxyindole O-methyltransferase

Actions: substrate

S-adenosyl-L-methionine + N-acetylserotonin = S-adenosyl-L-homocysteine + N-acetyl-5-methoxytryptamine

UniProt ID: P46597 Link_out
Gene: ASMT Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Minneman KP, Wurtman RJ: The pharmacology of the pineal gland. Annu Rev Pharmacol Toxicol. 1976;16:33-51. Pubmed

7. Indoleamine 2,3-dioxygenase

Actions: substrate

Tryptophan degradation

UniProt ID: P14902 Link_out
Gene: INDO Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ferry G, Ubeaud C, Lambert PH, Bertin S, Coge F, Chomarat P, Delagrange P, Serkiz B, Bouchet JP, Truscott RJ, Boutin JA: Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase. Biochem J. 2005 May 15;388(Pt 1):205-15. Pubmed

8. Myeloperoxidase

Actions: substrate, inhibitor

Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity

UniProt ID: P05164 Link_out
Gene: MPO Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ferry G, Ubeaud C, Lambert PH, Bertin S, Coge F, Chomarat P, Delagrange P, Serkiz B, Bouchet JP, Truscott RJ, Boutin JA: Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase. Biochem J. 2005 May 15;388(Pt 1):205-15. Pubmed

9. Cytochrome P450 19A1

Actions: inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Solute carrier family 22 member 8

Actions: inhibitor

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T: Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002 Oct;83(1):57-66. Pubmed
  2. Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on October 11, 2011 14:57

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.