T3DB: Coumarin

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (2)XML

Targets (2)

Record Information

Version

2.0

Creation Date

2014-09-11 05:20:21 UTC

Update Date

2014-12-24 20:26:58 UTC

Accession Number

T3D4875

Identification

Common Name

Coumarin

Class

Small Molecule

Description

Coumarin 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

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

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 Formula

C₉H₆O₂

Average Molecular Mass

146.143 g/mol

Monoisotopic Mass

146.037 g/mol

CAS Registry Number

91-64-5

IUPAC Name

2H-chromen-2-one

Traditional Name

coumarin

SMILES

O=C1OC2=CC=CC=C2C=C1

InChI Identifier

InChI=1S/C9H6O2/c10-9-6-5-7-3-1-2-4-8(7)11-9/h1-6H

InChI Key

InChIKey=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).

Kingdom

Organic compounds

Super Class

Phenylpropanoids and polyketides

Class

Coumarins and derivatives

Sub Class

Not Available

Direct Parent

Coumarins 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 Framework

Aromatic heteropolycyclic compounds

External Descriptors

coumarins (CHEBI:28794 )
coumarins (C05851 )
Phenylpropanoids (C05851 )
a coumarin (COUMARIN )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	71°C
Boiling Point	298°C (568.4°F)
Solubility	1.9 mg/mL
LogP	2.23

Predicted Properties

Property	Value	Source
Water Solubility	1 g/L	ALOGPS
logP	1.72	ALOGPS
logP	1.78	ChemAxon
logS	-2.2	ALOGPS
pKa (Strongest Basic)	-6.9	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	1	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	26.3 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	41.55 m³·mol⁻¹	ChemAxon
Polarizability	14.36 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-014v-6900000000-3e901733dc003512f338	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-00kb-8900000000-89e86d11a0dc2841af42	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-014i-7900000000-25bab36f91f71ac65817	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - EI-B (Non-derivatized)	splash10-02tj-9600000000-4a54f8d648a87a9c5811	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-014v-6900000000-3e901733dc003512f338	2017-09-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0gba-2900000000-12d24ebfbc2cbaa9d2e0	2017-07-27	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-0002-0900000000-6ef9288c71771dd56774	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-0006-9100000000-93154d9b40c4d0fdd1ae	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-014i-9000000000-72ec22913d1d574be75b	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - EI-B (HITACHI RMU-7L) , Positive	splash10-00kb-8900000000-89e86d11a0dc2841af42	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - EI-B (HITACHI RMU-6M) , Positive	splash10-014i-7900000000-25bab36f91f71ac65817	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - EI-B (JEOL JMS-AX-505-H) , Positive	splash10-02tj-9600000000-6e4062e14fc72534c96a	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - DI-ESI-qTof , Positive	splash10-015a-0900000100-6ae81e23a1a6770a9f59	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Linear Ion Trap , negative	splash10-000i-9200000000-38161abf759afe5aa970	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0002-0900000000-c06b97954c5a847401e8	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0002-1900000000-6f05165347e6221503b0	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0f6x-8900000000-6e9532ad6b20b76b3d4b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-9300000000-3f95abb339f5c1aea790	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-9200000000-c404268b480236aaf197	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , positive	splash10-0f6x-9500000000-da852779b618f093b767	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , positive	splash10-0006-9300000000-c29bd55b8ca9510aec2f	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , positive	splash10-0006-9100000000-161d49edf4310e8a785c	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0002-0900000000-3777f28f5438e1f09160	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0udi-0900000000-bfe432f57faff8d62318	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0089-0000800900-d301ec3931fa0374d57a	2017-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0002-0900000000-e5519a8faf9232fc0fcc	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0002-0900000000-a6dc6c6c3032891bd134	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0udi-4900000000-139cc9674e0b2836e441	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0002-0900000000-e1154242f99d56bc5ed4	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0002-0900000000-d6df7c01bbecf91182c9	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0udi-1900000000-961e88f9b351b2d27bec	2015-05-27	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-00kb-9700000000-7a649c1e257a7ad17b9d	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, CDCl₃, experimental)	Not Available	2012-12-04	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2014-09-20	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 15.09 MHz, CDCl₃, experimental)	Not Available	2014-09-23	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2021-10-10	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2021-10-10	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2021-10-10	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2021-10-10	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, CDCl₃, experimental)	Not Available	2012-12-05	View Spectrum

Toxicity Profile

Route of Exposure

Not Available

Mechanism of Toxicity

Not Available

Metabolism

Not Available

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (2)

Uses/Sources

Coumarin 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 Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

28794

BioCyc ID

COUMARIN

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

COU

ACToR ID

Not Available

Wikipedia Link

Coumarin

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.

MSDS

Link

General References

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 ]
International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Estrogen receptor

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

Type	Value	Assay Type	Assay Source
AC50	0.025 uM	Tox21_ERa_BLA_Agonist_ratio	Tox21/NCGC
AC50	1.67 uM	Tox21_ERa_LUC_BG1_Agonist	Tox21/NCGC

References

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 ]

Target Details

2. Cytochrome P450 2A6

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

Coumarin (T3D4875)

Structure for T3D4875: Coumarin

Targets

Binding/Activity Constants

References