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Record Information
Version2.0
Creation Date2014-09-11 05:20:21 UTC
Update Date2014-12-24 20:26:58 UTC
Accession NumberT3D4875
Identification
Common NameCoumarin
ClassSmall Molecule
DescriptionCoumarin is a chemical compound/poison found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. It has a sweet scent, readily recognised as the scent of newly-mown hay. It has clinical value as the precursor for several anticoagulants, notably warfarin. --Wikipedia. Coumarins, as a class, are comprised of numerous naturally occurring benzo-alpha-pyrone compounds with important and diverse physiological activities. The parent compound, coumarin, occurs naturally in many plants, natural spices, and foods such as tonka bean, cassia (bastard cinnamon or Chinese cinnamon), cinnamon, melilot (sweet clover), green tea, peppermint, celery, bilberry, lavender, honey (derived both from sweet clover and lavender), and carrots, as well as in beer, tobacco, wine, and other foodstuffs. Coumarin concentrations in these plants, spices, and foods range from <1 mg/kg in celery, 7000 mg/kg in cinnamon, and up to 87,000 mg/kg in cassia. An estimate of human exposure to coumarin from the diet has been calculated to be 0.02 mg/kg/day. Coumarin is used as an additive in perfumes and fragranced consumer products at concentrations ranging from <0.5% to 6.4% in fine fragrances to <0.01% in detergents. An estimate for systemic exposure of humans from the use of fragranced cosmetic products is 0.04 mg/kg BW/day, assuming complete dermal penetration. The use of coumarin as a food additive was banned by the FDA in 1954 based on reports of hepatotoxicity in rats. Due to its potential hepatotoxic effects in humans, the European Commission restricted coumarin from naturals as a direct food additive to 2 mg/kg food/day, with exceptions granting higher levels for alcoholic beverages, caramel, chewing gum, and certain 'traditional foods'. In addition to human exposure to coumarin from dietary sources and consumer products, coumarin is also used clinically as an antineoplastic and for the treatment of lymphedema and venous insufficiency. Exposure ranges from 11 mg/day for consumption of natural food ingredients to 7 g/day following clinical administration. Although adverse effects in humans following coumarin exposure are rare, and only associated with clinical doses, recent evidence indicates coumarin causes liver tumors in rats and mice and Clara cell toxicity and lung tumors in mice. The multiple effects as well as the ongoing human exposure to coumarin have resulted in a significant research effort focused on understanding the mechanism of coumarin induced toxicity/carcinogenicity and its human relevance. These investigations have revealed significant species differences in coumarin metabolism and toxicity such that the mechanism of coumarin induced effects in rodents, and the relevance of these findings for the safety assessment of coumarin exposure in humans are now better understood. In October 2004, the European Food Safety Authority (EFSA, 2004) reviewed coumarin to establish a tolerable daily intake (TDI) in foods. EFSA issued an opinion indicating that coumarin is not genotoxic, and that a threshold approach to safety assessment was most appropriate. EFSA recommended a TDI of 0 to 0.1 mg/kg BW/day. Including dietary contributions, the total human exposure is estimated to be 0.06 mg/kg/day. As a pharmaceutical, coumarin has been used in diverse applications with a wide variety of dosing regimens. Unlike coumadin and other coumarin derivatives, coumarin has no anti-coagulant activity. However, at low doses (typically 7 to 10 mg/day), coumarin has been used as a 'venotonic' to promote vein health and small venule blood flow. Additionally, coumarin has been used clinically in the treatment of high-protein lymphedema of various etiologies. (1).
Compound Type
  • Cosmetic Toxin
  • Ester
  • Food Toxin
  • Fragrance Toxin
  • Household Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Plant Toxin
Chemical Structure
Thumb
Synonyms
Synonym
1, 2-Benzopyrone
2-Oxo-1,2-benzopyran
2-Oxo-2H-1-Benzopyran
2H-1-Benzopyran-2-one
2H-Benzo[b]pyran-2-one
2H-Chromen-2-one
5,6-Benzo-2-pyrone
Benzo-a-pyrone
Benzo-alpha-pyrone
cis-O-Coumarinic acid lactone
Coumarine
Coumarinic anhydride
Cumarin
Kumarin
O-Hydroxycinnamic acid lactone
O-Hydroxycinnamic lactone
O-Hydroxyzimtsaure-lacton
Rattex
Tonka bean camphor
{2H-Benzo[b]pyran-2-one}
Chemical FormulaC9H6O2
Average Molecular Mass146.143 g/mol
Monoisotopic Mass146.037 g/mol
CAS Registry Number91-64-5
IUPAC Name2H-chromen-2-one
Traditional Namecoumarin
SMILESO=C1OC2=CC=CC=C2C=C1
InChI IdentifierInChI=1S/C9H6O2/c10-9-6-5-7-3-1-2-4-8(7)11-9/h1-6H
InChI KeyInChIKey=ZYGHJZDHTFUPRJ-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as coumarins and derivatives. These are polycyclic aromatic compounds containing a 1-benzopyran moiety with a ketone group at the C2 carbon atom (1-benzopyran-2-one).
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassCoumarins and derivatives
Sub ClassNot Available
Direct ParentCoumarins and derivatives
Alternative Parents
Substituents
  • Coumarin
  • 1-benzopyran
  • Benzopyran
  • Pyranone
  • Benzenoid
  • Pyran
  • Heteroaromatic compound
  • Lactone
  • Oxacycle
  • Organoheterocyclic compound
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point71°C
Boiling Point298°C (568.4°F)
Solubility1.9 mg/mL
LogP2.23
Predicted Properties
PropertyValueSource
Water Solubility1 g/LALOGPS
logP1.72ALOGPS
logP1.78ChemAxon
logS-2.2ALOGPS
pKa (Strongest Basic)-6.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area26.3 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity41.55 m³·mol⁻¹ChemAxon
Polarizability14.36 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-014v-6900000000-3e901733dc003512f338JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-00kb-8900000000-89e86d11a0dc2841af42JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-014i-7900000000-25bab36f91f71ac65817JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-02tj-9600000000-4a54f8d648a87a9c5811JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-014v-6900000000-3e901733dc003512f338JSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0gba-2900000000-12d24ebfbc2cbaa9d2e0JSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0002-0900000000-6ef9288c71771dd56774JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-0006-9100000000-93154d9b40c4d0fdd1aeJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-014i-9000000000-72ec22913d1d574be75bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI RMU-7L) , Positivesplash10-00kb-8900000000-89e86d11a0dc2841af42JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (HITACHI RMU-6M) , Positivesplash10-014i-7900000000-25bab36f91f71ac65817JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (JEOL JMS-AX-505-H) , Positivesplash10-02tj-9600000000-6e4062e14fc72534c96aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - DI-ESI-qTof , Positivesplash10-015a-0900000100-6ae81e23a1a6770a9f59JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , negativesplash10-000i-9200000000-38161abf759afe5aa970JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-0900000000-c06b97954c5a847401e8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-1900000000-6f05165347e6221503b0JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0f6x-8900000000-6e9532ad6b20b76b3d4bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0006-9300000000-3f95abb339f5c1aea790JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0006-9200000000-c404268b480236aaf197JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-0f6x-9500000000-da852779b618f093b767JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-0006-9300000000-c29bd55b8ca9510aec2fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-0006-9100000000-161d49edf4310e8a785cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0002-0900000000-3777f28f5438e1f09160JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0udi-0900000000-bfe432f57faff8d62318JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0089-0000800900-d301ec3931fa0374d57aJSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-0900000000-e5519a8faf9232fc0fccJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0002-0900000000-a6dc6c6c3032891bd134JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0udi-4900000000-139cc9674e0b2836e441JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0900000000-e1154242f99d56bc5ed4JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0002-0900000000-d6df7c01bbecf91182c9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0udi-1900000000-961e88f9b351b2d27becJSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-00kb-9700000000-7a649c1e257a7ad17b9dJSpectraViewer | MoNA
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityNot Available
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (2)
Uses/SourcesCoumarin is a chemical compound/poison found in many plants, notably in high concentration in the tonka bean, woodruff, and bison grass. The parent compound, coumarin, occurs naturally in many plants, natural spices, and foods such as tonka bean, cassia (bastard cinnamon or Chinese cinnamon), cinnamon, melilot (sweet clover), green tea, peppermint, celery, bilberry, lavender, honey (derived both from sweet clover and lavender), and carrots, as well as in beer, tobacco, wine, and other foodstuffs. Coumarin is used as an additive in perfumes and fragranced consumer products at concentrations ranging from <0.5% to 6.4% in fine fragrances to <0.01% in detergents. In addition to human exposure to coumarin from dietary sources and consumer products, coumarin is also used clinically as an antineoplastic and for the treatment of lymphedema and venous insufficiency. The multiple effects as well as the ongoing human exposure to coumarin have resulted in a significant research effort focused on understanding the mechanism of coumarin induced toxicity/carcinogenicity and its human relevance. As a pharmaceutical, coumarin has been used in diverse applications with a wide variety of dosing regimens. However, at low doses (typically 7 to 10 mg/day), coumarin has been used as a 'venotonic' to promote vein health and small venule blood flow. Additionally, coumarin has been used clinically in the treatment of high-protein lymphedema of various etiologies.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB04665
HMDB IDHMDB01218
PubChem Compound ID323
ChEMBL IDCHEMBL6466
ChemSpider ID13848793
KEGG IDC05851
UniProt IDNot Available
OMIM ID
ChEBI ID28794
BioCyc IDCOUMARIN
CTD IDNot Available
Stitch IDNot Available
PDB IDCOU
ACToR IDNot Available
Wikipedia LinkCoumarin
References
Synthesis Reference

Ernst-Christian Witte, Peter Neubert, Androniki Roesch, “2H-1-benzopyran-2-one derivatives, processes for the preparation thereof and pharmaceutical compositions containing them.” U.S. Patent US4670439, issued May, 1974.

MSDSLink
General References
  1. Felter SP, Vassallo JD, Carlton BD, Daston GP: A safety assessment of coumarin taking into account species-specificity of toxicokinetics. Food Chem Toxicol. 2006 Apr;44(4):462-75. Epub 2005 Oct 3. [16203076 ]
  2. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Zinc ion binding
Specific Function:
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. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.025 uMTox21_ERa_BLA_Agonist_ratioTox21/NCGC
AC501.67 uMTox21_ERa_LUC_BG1_AgonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Steroid hydroxylase activity
Specific Function:
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.
Gene Name:
CYP2A6
Uniprot ID:
P11509
Molecular Weight:
56501.005 Da