T3DB: Carbamazepine

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (14)XML

Targets (14)

Record Information

Version

2.0

Creation Date

2009-07-21 20:27:10 UTC

Update Date

2014-12-24 20:25:52 UTC

Accession Number

T3D2826

Identification

Common Name

Carbamazepine

Class

Small Molecule

Description

An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar.

Compound Type

Amine
Analgesic
Analgesic, Non-Narcotic
Anticonvulsant
Antimanic Agent
Drug
Metabolite
Organic Compound
Synthetic Compound

Chemical Structure

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

Synonyms

Synonym
5-Carbamoyl-5H-dibenz(b,f)azepine
5-Carbamoyl-5H-dibenzo(b,F)azepine
5-Carbamoyl-5H-dibenz[b,F]azepine
5-Carbamyl-5H-dibenzo(b,F)azepine
5H-Dibenz(b,F)azepine-5-carboxamide
Actebral
Anleptic
Biston
Carbamat
Carbamazepen
Carbamazepin
Carbamazepina
Carbamazépine
Carbamazepinum
Carbamezepine
Carbatrol
CBZ
Epitol
Equetro
Neurotop
TEGretol
TEGretol Chewtabs
TEGretol-CR
TEGretol-XR
Teril
Timonil
Versitol
Versizur

Chemical Formula

C₁₅H₁₂N₂O

Average Molecular Mass

236.269 g/mol

Monoisotopic Mass

236.095 g/mol

CAS Registry Number

298-46-4

IUPAC Name

2-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,9,11,13-heptaene-2-carboxamide

Traditional Name

2-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,9,11,13-heptaene-2-carboxamide

SMILES

OC(=N)N1C2=CC=CC=C2C=CC2=CC=CC=C12

InChI Identifier

InChI=1S/C15H12N2O/c16-15(18)17-13-7-3-1-5-11(13)9-10-12-6-2-4-8-14(12)17/h1-10H,(H2,16,18)

InChI Key

InChIKey=FFGPTBGBLSHEPO-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as dibenzazepines. Dibenzazepines are compounds with two benzene rings connected by an azepine ring. Azepine is an unsaturated seven-member heterocycle with one nitrogen atom replacing a carbon atom.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Benzazepines

Sub Class

Dibenzazepines

Direct Parent

Dibenzazepines

Alternative Parents

Substituents

Dibenzazepine
Azepine
Benzenoid
Urea
Carbonic acid derivative
Azacycle
Organic nitrogen compound
Organic oxygen compound
Organopnictogen compound
Organic oxide
Hydrocarbon derivative
Organooxygen compound
Organonitrogen compound
Carbonyl group
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

ureas (CHEBI:3387 )
dibenzoazepine (CHEBI:3387 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

EC 3.5.1.98 (histone deacetylase) inhibitor

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	204-206°C
Boiling Point	Not Available
Solubility	17.7 mg/L
LogP	2.45

Predicted Properties

Property	Value	Source
Water Solubility	0.15 g/L	ALOGPS
logP	2.1	ALOGPS
logP	2.77	ChemAxon
logS	-3.2	ALOGPS
pKa (Strongest Acidic)	15.96	ChemAxon
pKa (Strongest Basic)	-3.8	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	1	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	46.33 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	71.89 m³·mol⁻¹	ChemAxon
Polarizability	25 Å³	ChemAxon
Number of Rings	3	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
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0006-3970000000-8f03b4d1ea6cec6641ec	2017-09-01	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 - LC-ESI-qTof , Positive	splash10-000f-1940000000-9677ddf985ba43e76817	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-000f-0930000000-b2a70bea75cef0c24556	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-0006-2900000000-86f35079f274f4014c3d	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-000i-0090000000-be63f70e101a786a369b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-0910000000-f171a56d3bbeaef24ff4	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-0900000000-a82def037961e9b94a9a	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-0900000000-484ce005b4ae5d01fc2a	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-0006-0900000000-a6992953eac16c120e74	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0900000000-7a1010be5231131649eb	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-000i-0090000000-51ef94c86cca9b541780	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-000i-0490000000-4484ac1671912bc60ba9	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0910000000-e5ca06888593ada95f15	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0900000000-5742023f1e263fb40066	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0900000000-f27fb9d17b228cc328b8	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0900000000-63c554c485fd1d117082	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-000i-0090000000-c6c89d3e663885fcc080	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-000i-0490000000-8a1d8d7b932f1b0ad45e	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0910000000-843efaf5294cb110e0b9	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0900000000-7eb2855f73a1ed729181	2017-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-000i-0290000000-926be8d54e58a26d40d3	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-000f-0950000000-68b3fa7ce7380dc8311e	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0006-1900000000-60a9fc188e8c79505dee	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-8960000000-8aa13e4d27b1afb8662d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0006-2900000000-6d502f01257a774384bf	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9500000000-3d22d3677d67ba94c4ac	2016-08-03	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0006-1910000000-4b2dc85e8da73b101ed2	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Oral. In clinical studies, carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, it has been observed that the suspension is somewhat faster absorbed. Furthermore, the extended-release tablet is slightly slower than the conventional tablet. The bioavailability of the extended-release tablet is 89%, compared to the suspension. Plasma levels of carbamazepine are variable. The time to peak concentration for the different formulations are as follows: Suspension = 1.5 hours; Conventional tablets = 4-5 hours; Extended-release tablets = 3-12 hours.

Mechanism of Toxicity

Carbamazepine inhibits sustained repetitive firing by blocking use-dependent sodium channels. Pain relief is believed to be associated with blockade of synaptic transmission in the trigeminal nucleus and seizure control with reduction of post-tetanic potentiation of synaptic transmission in the spinal cord. Carbamazepine also possesses anticholinergic, central antidiuretic, antiarrhythmic, muscle relaxant, antidepressant (possibly through blockade of norepinephrine release), sedative, and neuromuscular-blocking properties.

Metabolism

Hepatic. CYP3A4 is the primary isoform responsible for the formation of carbamazepine-10,11-epoxide. This metabolite is active and shown to be equipotent to carbamazepine as an anticonvulsant. Carbamazepine is more rapidly metabolized to the aforementioned metabolite in younger patients than in adults. It also undergoes glucuronidation via UGT2B7, however this finding has been disputed. Route of Elimination: 72% of the dose is in the urine while 28% is in the feces. Hydroxylated and conjugated metabolites are largely what was recovered in the urine. 3% of the dose is recovered as unchanged carbamazepine. Half Life: Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses.

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the treatment of epilepsy and pain associated with true trigeminal neuralgia.

Minimum Risk Level

Not Available

Health Effects

May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.

Symptoms

Mild ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations. Severe intoxications may produce coma, seizures, respiratory depression, and hypotension

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote. (4)

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

3387

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Carbamazepine

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Carbamazepine

References

Synthesis Reference

Ketan Dhansukhlal Vyas, Wajid Sajjad Jafri, Ashok Krishna Kulkarni, “Process for preparing carbamazepine from iminostilbene.” U.S. Patent US6245908, issued February, 1998.

MSDS

Link

General References

Staines AG, Coughtrie MW, Burchell B: N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. J Pharmacol Exp Ther. 2004 Dec;311(3):1131-7. Epub 2004 Aug 3. [15292462 ]
Sisodiya SM, Goldstein DB: Drug resistance in epilepsy: more twists in the tale. Epilepsia. 2007 Dec;48(12):2369-70. [18088268 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Targets

Target Details

1. Sodium channel protein type 5 subunit alpha

General Function:: Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:: This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Gene Name:: SCN5A
Uniprot ID:: Q14524
Molecular Weight:: 226937.475 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

2. 5-hydroxytryptamine receptor 1A

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
Gene Name:: HTR1A
Uniprot ID:: P08908
Molecular Weight:: 46106.335 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50003659

References

Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS: Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr. 1998 Mar;178:440-66. [9686407 ]

Target Details

3. D(1A) dopamine receptor

General Function:: G-protein coupled amine receptor activity
Specific Function:: Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name:: DRD1
Uniprot ID:: P21728
Molecular Weight:: 49292.765 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50003659

References

Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS: Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr. 1998 Mar;178:440-66. [9686407 ]

Target Details

4. Histamine H1 receptor

General Function:: Histamine receptor activity
Specific Function:: In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Gene Name:: HRH1
Uniprot ID:: P35367
Molecular Weight:: 55783.61 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50003659

References

Kanba S, Richelson E: Histamine H1 receptors in human brain labelled with [3H]doxepin. Brain Res. 1984 Jun 18;304(1):1-7. [6146381 ]

Target Details

5. Nuclear receptor subfamily 1 group I member 2

General Function:: Zinc ion binding
Specific Function:: Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:: NR1I2
Uniprot ID:: O75469
Molecular Weight:: 49761.245 Da

References

Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [14977870 ]

Target Details

6. Sodium channel protein type 4 subunit alpha

General Function:: Voltage-gated sodium channel activity
Specific Function:: This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle.
Gene Name:: SCN4A
Uniprot ID:: P35499
Molecular Weight:: 208059.175 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	52 uM	Not Available	BindingDB 50003659

References

Yang J, Gharagozloo P, Yao J, Ilyin VI, Carter RB, Nguyen P, Robledo S, Woodward RM, Hogenkamp DJ: 3-(4-phenoxyphenyl)pyrazoles: a novel class of sodium channel blockers. J Med Chem. 2004 Mar 11;47(6):1547-52. [14998340 ]

Target Details

7. Sodium channel protein type 9 subunit alpha

General Function:: Voltage-gated sodium channel activity
Specific Function:: Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain (By similarity).
Gene Name:: SCN9A
Uniprot ID:: Q15858
Molecular Weight:: 226370.175 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	22 uM	Not Available	BindingDB 50003659

References

London C, Hoyt SB, Parsons WH, Williams BS, Warren VA, Tschirret-Guth R, Smith MM, Priest BT, McGowan E, Martin WJ, Lyons KA, Li X, Karanam BV, Jochnowitz N, Garcia ML, Felix JP, Dean B, Abbadie C, Kaczorowski GJ, Duffy JL: Imidazopyridines: a novel class of hNav1.7 channel blockers. Bioorg Med Chem Lett. 2008 Mar 1;18(5):1696-701. doi: 10.1016/j.bmcl.2008.01.047. Epub 2008 Jan 18. [18243692 ]

Target Details

8. Androgen receptor

General Function:: Zinc ion binding
Specific Function:: Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:: AR
Uniprot ID:: P10275
Molecular Weight:: 98987.9 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	2.93 uM	Tox21_AR_BLA_Agonist_ratio	Tox21/NCGC
AC50	7.70 uM	Tox21_AR_LUC_MDAKB2_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

9. Bile acid receptor

General Function:: Zinc ion binding
Specific Function:: Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.
Gene Name:: NR1H4
Uniprot ID:: Q96RI1
Molecular Weight:: 55913.915 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	3.66 uM	OT_SRC1_SRC1FXR_1440	Odyssey Thera

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

10. Hepatocyte nuclear factor 4-alpha

General Function:: Zinc ion binding
Specific Function:: Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine.
Gene Name:: HNF4A
Uniprot ID:: P41235
Molecular Weight:: 52784.205 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	4.29 uM	ATG_HNF4a_TRANS	Attagene

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

11. Nuclear receptor ROR-beta

General Function:: Zinc ion binding
Specific Function:: Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Considered to have intrinsic transcriptional activity, have some natural ligands such as all-trans retinoic acid (ATRA) and other retinoids which act as inverse agonists repressing the transcriptional activity. Required for normal postnatal development of rod and cone photoreceptor cells. Modulates rod photoreceptors differentiation at least by inducing the transcription factor NRL-mediated pathway. In cone photoreceptor cells, regulates transcription of OPN1SW. Involved in the regulation of the period length and stability of the circadian rhythm. May control cytoarchitectural patterning of neocortical neurons during development. May act in a dose-dependent manner to regulate barrel formation upon innervation of layer IV neurons by thalamocortical axons. May play a role in the suppression of osteoblastic differentiation through the inhibition of RUNX2 transcriptional activity (By similarity).Isoform 1 is critical for hindlimb motor control and for the differentiation of amacrine and horizontal cells in the retina. Regulates the expression of PTF1A synergistically with FOXN4 (By similarity).
Gene Name:: RORB
Uniprot ID:: Q92753
Molecular Weight:: 53219.385 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	6.72 uM	ATG_RORb_TRANS	Attagene

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

12. Estrogen-related receptor gamma

General Function:: Zinc ion binding
Specific Function:: Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle.
Gene Name:: ESRRG
Uniprot ID:: P62508
Molecular Weight:: 51305.485 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	7.03 uM	ATG_ERRg_TRANS	Attagene

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

13. Glucocorticoid receptor

General Function:: Zinc ion binding
Specific Function:: Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression.
Gene Name:: NR3C1
Uniprot ID:: P04150
Molecular Weight:: 85658.57 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	7.32 uM	Tox21_GR_BLA_Agonist_ratio	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

14. Nuclear receptor subfamily 4 group A member 2

General Function:: Zinc ion binding
Specific Function:: Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity).
Gene Name:: NR4A2
Uniprot ID:: P43354
Molecular Weight:: 66590.375 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	7.55 uM	ATG_NURR1_TRANS	Attagene

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 ]

Carbamazepine (T3D2826)

Structure for T3D2826: Carbamazepine

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