Valproic acid (T3D2558)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (20)XML
Targets (20)
Record Information
Version2.0
Creation Date2009-07-05 02:58:24 UTC
Update Date2014-12-24 20:25:42 UTC
Accession NumberT3D2558
Identification
Common NameValproic acid
ClassSmall Molecule
DescriptionValproic acid (VPA) is considered to be a drug of first choice and one of the most frequently-prescribed antiepileptic drugs worldwide for the therapy of generalized and focal epilepsies, including special epileptic. It is a broad-spectrum antiepileptic drug and is usually well tolerated. Rarely, serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulopathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy, but there is still a lack of knowledge about the incidence and occurrence of these special side effects. VPA has been approved for stabilization of manic episodes in patients with bipolar disorder. It is also used to treat migraine headaches and schizophrenia. As the use of VPA increases, the number of both accidental and intentional exposures increases. This is paralleled by more reports of VPA-induced toxicity. VPA is relatively contraindicated in pregnancy due to its teratogenicity. It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate teratogenic problems. Women who become pregnant whilst taking valproate should be counselled as to its risks. VPA is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. Patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a median 75% reduction in latent HIV infection. VPA is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. (6, 7).
Compound Type
  • Anticonvulsant
  • Antimanic Agent
  • Drug
  • Enzyme Inhibitor
  • Food Toxin
  • GABA Agent
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
2-n-propyl-n-valeric acid
2-PROPYL-pentanoic acid
2-Propylpentanoic acid
2-Propylvaleric acid
4-heptanecarboxylic acid
Acide valproique
Acido valproico
Acidum valproicum
Convulex
Depacon
Depakene
Depakine
Depakote
Depakote ER
Deprakine
di-n-propylacetic acid
Encorate
Epilim
Epival
Valproate
Chemical FormulaC8H16O2
Average Molecular Mass144.211 g/mol
Monoisotopic Mass144.115 g/mol
CAS Registry Number99-66-1
IUPAC Name2-propylpentanoic acid
Traditional Namevalproic acid
SMILESCCCC(CCC)C(O)=O
InChI IdentifierInChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
InChI KeyInChIKey=NIJJYAXOARWZEE-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as methyl-branched fatty acids. These are fatty acids with an acyl chain that has a methyl branch. Usually, they are saturated and contain only one or more methyl group. However, branches other than methyl may be present.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acids and conjugates
Direct ParentMethyl-branched fatty acids
Alternative Parents
Substituents
  • Methyl-branched fatty acid
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Brain
  • Liver
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite crystals.
Experimental Properties
PropertyValue
Melting Point120 - 130°C
Boiling Point222°C
Solubility1.3 mg/mL
LogP2.75
Predicted Properties
PropertyValueSource
Water Solubility2.36 g/LALOGPS
logP2.54ALOGPS
logP2.8ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)5.14ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity40.25 m³·mol⁻¹ChemAxon
Polarizability17 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-004m-9300000000-e66da5fefd079f7426a42017-08-28View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-00b9-9100000000-7bb11c5d52ffa09851f82017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, N/A (Annotated)splash10-0udi-2900000000-156413e81733a6236c1f2012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, N/A (Annotated)splash10-0f6y-2900000000-a769cafb885b78532cac2012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, N/A (Annotated)splash10-0gbj-7900000000-46a522b9a26459334f5a2012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-0006-0900000000-39a45d4e3201082d9d892012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-0002-9000000000-4ddd957d8c8dc2b1de032012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-0006-0900000000-6ba582ae102c4721034d2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-0006-0900000000-58d9ba88010f1b370c582012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negativesplash10-0006-3900000000-2d1032d7e8ac58235b4f2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negativesplash10-0a4j-9000000000-0d39870bc4521a42c50a2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negativesplash10-00di-9000000000-3c4e21b69b8877d6df3e2012-08-31View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0006-0900000000-39a45d4e3201082d9d892017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0002-9000000000-4ddd957d8c8dc2b1de032017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0006-0900000000-6ba582ae102c4721034d2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0006-0900000000-58d9ba88010f1b370c582017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0006-3900000000-2d1032d7e8ac58235b4f2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-0a4j-9000000000-0d39870bc4521a42c50a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-00di-9000000000-3c4e21b69b8877d6df3e2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , negativesplash10-0006-0900000000-5b83f0d6c36f8249285a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 20V, Negativesplash10-0006-0900000000-51a760d50a87d131ad672021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-3900000000-be0e79e3b65dad2e2d082017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0005-9500000000-37d8981251a94cfd51e32017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9000000000-b63be8686bbf9a96b2ba2017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-3900000000-25f23d80c7431c074a742017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0005-9500000000-144b6cc9fea5bae4f2692017-07-26View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-052e-9100000000-eb5e97329782125f66152017-07-26View Spectrum
MSMass Spectrum (Electron Ionization)splash10-0fk9-9300000000-1a0314ea63d5a3c9bba12014-09-20View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, 90 MHz, CDCl3, experimental)Not Available2014-09-20View Spectrum
1D NMR13C NMR Spectrum (1D, 25.16 MHz, CDCl3, experimental)Not Available2014-09-23View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2012-12-05View Spectrum
Toxicity Profile
Route of ExposureInhalation. Rapid absorption from gastrointestinal tract. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Food has a greater influence on the rate of absorption of the Depakote tablet (increases Tmax from 4 to 8 hours) than on the absorption of Depakote sprinkle capsules (increase Tmax from 3.3 to 4.8 hours). Furthermore, studies suggest that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control.
Mechanism of ToxicityValproic Acid binds to and inhibits GABA transaminase. This leads to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. Acute poisoning by VPA can lead to severe CNS depression including coma, confusion, somnolence, dizziness or hallucinations. Hypotension, respiratory depression and hypo/hyperthermia are also common. VPA is also hepatotoxic, which is likely due to its mitochondrial toxicity. VPA appears to exert its mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which leads to apoptosis (17). VPA is contraindicated in pregnancy due to its teratogenicity. VPA is a known folate antagonist, which can cause neural tube defects in developing fetuses. Thus, folic acid supplements in pregnant women may alleviate teratogenic problems associated with VPA use. VPA and its metabolites inhibit the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate (through direct inhibition of alpha-ketoglutarate dehydrogenase) and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. VPA has been shown to downregulate levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate. It has also been shown to upregulate H2O2 and homocysteine. Elevated levels of H2O2 negatively affect the NADPH reducing system for dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) (18).
MetabolismValproic acid is rapidly absorbed from gastrointestinal tract. Valproic acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. These products include 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and several coenzyme A (CoA) derivatives including VPA-CoA, and delta 2,3 VPE-CoA. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine (1). Half Life: 9-16 hours (following oral administration of 250 mg to 1000 mg).
Toxicity ValuesOral, mouse: LD50 = 1098 mg/kg; Oral, rat: LD50 = 670 mg/kg. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome (1).
Minimum Risk LevelNot Available
Health EffectsValproic acid causes hyperammonemia, which can lead to brain damage. Rarely, it can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome (23). May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. Acute overdoses of VPA can lead to hypo/hyperthermia, tachycardia, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Extended use of VPA can cause hepatotoxicity. Allopecia, anorexia, renal failure, tremors and miosis are also associated with chronic toxicity. VPA is a known teratogen (due to folate antagonism). The teratogenicity of VPA is mostly found at genetic and somatic levels, causing teratogenesis involving neural tube defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta.
SymptomsAcute toxicity symptoms include hypo/hyperthermia, tachycardia, hepatic toxicity, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Allopecia, anorexia, liver toxicity, renal failure, tremors and miosis are also associated with chronic toxicity.
TreatmentIn case of acute oral exposure, administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of the compound if it can be performed soon after ingestion (generally within 1 hour). Protect the patient’s airway by placement in Trendelenburg position (head down) and on their left side (left lateral decubitus position) or by endotracheal intubation. Control any seizures first. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children (19). In case of inhalation, move patient to fresh air, monitor for respiratory distress. If the exposure occurred via eye contact, irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Remove contaminated clothing and wash exposed area thoroughly with soap and water if the exposure occurred via dermal contact. (20).
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00313
HMDB IDHMDB01877
PubChem Compound ID3121
ChEMBL IDCHEMBL109
ChemSpider ID3009
KEGG IDC07185
UniProt IDNot Available
OMIM ID125480176860188550237310609442
ChEBI ID39867
BioCyc IDNot Available
CTD IDNot Available
Stitch IDValproic acid
PDB ID2PP
ACToR IDNot Available
Wikipedia LinkValproic_Acid
References
Synthesis Reference

Daniel Aubert, Francis Blanc, Henri Desmolin, Michel Morre, Lucette Sindely, “Valproic acid preparations.” U.S. Patent US5017613, issued January, 1965.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Rosenberg G: The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103. [17514356 ]
  3. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM: Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55. [16099290 ]
  4. Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G: Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines. Int J Oncol. 2007 Mar;30(3):573-82. [17273758 ]
  5. Valentini A, Gravina P, Federici G, Bernardini S: Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol Ther. 2007 Feb;6(2):185-91. Epub 2007 Feb 5. [17218782 ]
  6. Gerstner T, Bell N, Konig S: Oral valproic acid for epilepsy--long-term experience in therapy and side effects. Expert Opin Pharmacother. 2008 Feb;9(2):285-92. doi: 10.1517/14656566.9.2.285 . [18201150 ]
  7. Russell S: Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr. 2007 Apr;19(2):206-10. [17496767 ]
  8. Bell EC, Willson MC, Wilman AH, Dave S, Silverstone PH: Differential effects of chronic lithium and valproate on brain activation in healthy volunteers. Hum Psychopharmacol. 2005 Aug;20(6):415-24. [16106488 ]
  9. Nemeroff CB: The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull. 2003;37(4):133-46. [15131523 ]
  10. Sztajnkrycer MD: Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40(6):789-801. [12475192 ]
  11. Seyfert S, Bernarding J, Braun J: Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy. Neuroradiology. 2003 May;45(5):295-9. Epub 2003 Mar 27. [12669157 ]
  12. Eyal S, Lamb JG, Smith-Yockman M, Yagen B, Fibach E, Altschuler Y, White HS, Bialer M: The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver. Br J Pharmacol. 2006 Oct;149(3):250-60. Epub 2006 Aug 7. [16894351 ]
  13. Loscher W: Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669-94. [12269861 ]
  14. Huang YL, Hong HS, Wang ZW, Kuo TT: Fatal sodium valproate-induced hypersensitivity syndrome with lichenoid dermatitis and fulminant hepatitis. J Am Acad Dermatol. 2003 Aug;49(2):316-9. [12894087 ]
  15. Anderson GD, Temkin NR, Chandler WL, Winn HR: Effect of valproate on hemostatic function in patients with traumatic brain injury. Epilepsy Res. 2003 Dec;57(2-3):111-9. [15013052 ]
  16. Ho PC, Abbott FS, Zanger UM, Chang TK: Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogenomics J. 2003;3(6):335-42. [14597963 ]
  17. Jafarian I, Eskandari MR, Mashayekhi V, Ahadpour M, Hosseini MJ: Toxicity of valproic acid in isolated rat liver mitochondria. Toxicol Mech Methods. 2013 Oct;23(8):617-23. doi: 10.3109/15376516.2013.821567. Epub 2013 Aug 1. [23819490 ]
  18. Hsieh CL, Wang HE, Tsai WJ, Peng CC, Peng RY: Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model. Toxicology. 2012 Jan 27;291(1-3):32-42. doi: 10.1016/j.tox.2011.10.015. Epub 2011 Oct 25. [22051200 ]
  19. Lheureux PE, Hantson P: Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009 Feb;47(2):101-11. doi: 10.1080/15563650902752376. [19280426 ]
  20. Rumack BH (2009). POISINDEX(R) Information System. Englewood, CO: Micromedex, Inc. CCIS Volume 141, edition expires Aug, 2009.
  21. O'Neil MJ (ed) (2001). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc.
  22. FDA label
  23. Wikipedia. Valproic Acid. Last Updated 30 July 2009. [Link]
  24. Drugs.com [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Histone deacetylase 9
General Function:
Transcription factor binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription.Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter.
Gene Name:
HDAC9
Uniprot ID:
Q9UKV0
Molecular Weight:
111296.29 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>2000 uMNot AvailableBindingDB 50003616
References
  1. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM: Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004 May 21;18(8):1101-8. [15166525 ]
  2. Michaelis M, Kohler N, Reinisch A, Eikel D, Gravemann U, Doerr HW, Nau H, Cinatl J Jr: Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid. Biochem Pharmacol. 2004 Aug 1;68(3):531-8. [15242819 ]
  3. Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM: Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J. 2004;4(5):336-44. [15289798 ]
  4. Stockhausen MT, Sjolund J, Manetopoulos C, Axelson H: Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Br J Cancer. 2005 Feb 28;92(4):751-9. [15685243 ]
  5. Beutler AS, Li S, Nicol R, Walsh MJ: Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15. [15850602 ]
  6. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
2. 4-aminobutyrate aminotransferase, mitochondrial
General Function:
Succinate-semialdehyde dehydrogenase binding
Specific Function:
Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-alanine.
Gene Name:
ABAT
Uniprot ID:
P80404
Molecular Weight:
56438.405 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. 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 ]
  3. Loscher W: Anticonvulsant and biochemical effects of inhibitors of GABA aminotransferase and valproic acid during subchronic treatment in mice. Biochem Pharmacol. 1982 Mar 1;31(5):837-42. [6805473 ]
  4. Ha JH, Lee DU, Lee JT, Kim JS, Yong CS, Kim JA, Ha JS, Huh K: 4-Hydroxybenzaldehyde from Gastrodia elata B1. is active in the antioxidation and GABAergic neuromodulation of the rat brain. J Ethnopharmacol. 2000 Nov;73(1-2):329-33. [11025174 ]
  5. Semba J, Kuroda Y, Takahashi R: Potential antidepressant properties of subchronic GABA transaminase inhibitors in the forced swimming test in mice. Neuropsychobiology. 1989;21(3):152-6. [2559361 ]
Target Details
3. Histone deacetylase 2
General Function:
Transcription factor binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A.
Gene Name:
HDAC2
Uniprot ID:
Q92769
Molecular Weight:
55363.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5062 uMNot AvailableBindingDB 50003616
References
  1. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M: The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003 Jul 1;22(13):3411-20. [12840003 ]
  2. Gottlicher M: Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol. 2004;83 Suppl 1:S91-2. [15124690 ]
  3. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
4. 2-oxoglutarate dehydrogenase, mitochondrial
General Function:
Thiamine pyrophosphate binding
Specific Function:
The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). It contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3).
Gene Name:
OGDH
Uniprot ID:
Q02218
Molecular Weight:
115934.37 Da
References
  1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216. [12847559 ]
Target Details
5. Alcohol dehydrogenase [NADP(+)]
General Function:
L-glucuronate reductase activity
Specific Function:
Catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols. Catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol. Has broad substrate specificity. In vitro substrates include succinic semialdehyde, 4-nitrobenzaldehyde, 1,2-naphthoquinone, methylglyoxal, and D-glucuronic acid. Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN).
Gene Name:
AKR1A1
Uniprot ID:
P14550
Molecular Weight:
36572.71 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5050.1 uMNot AvailableBindingDB 50003616
References
  1. Alexiou P, Demopoulos VJ: A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. J Med Chem. 2010 Nov 11;53(21):7756-66. doi: 10.1021/jm101008m. [20936791 ]
Target Details
6. Fas-binding factor 1
General Function:
Not Available
Specific Function:
Keratin-binding protein required for epithelial cell polarization. Involved in apical junction complex (AJC) assembly via its interaction with PARD3. Required for ciliogenesis.
Gene Name:
FBF1
Uniprot ID:
Q8TES7
Molecular Weight:
125445.19 Da
References
  1. Dasgupta A, Emerson L: Interaction of valproic acid with nonsteroidal antiinflammatory drugs mefenamic acid and fenoprofen in normal and uremic sera: lack of interaction in uremic sera due to the presence of endogenous factors. Ther Drug Monit. 1996 Dec;18(6):654-9. [8946661 ]
Target Details
7. Histone deacetylase 1
General Function:
Transcription regulatory region sequence-specific dna binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation.
Gene Name:
HDAC1
Uniprot ID:
Q13547
Molecular Weight:
55102.615 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5039 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
8. Histone deacetylase 3
General Function:
Transcription factor binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803).
Gene Name:
HDAC3
Uniprot ID:
O15379
Molecular Weight:
48847.385 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50161 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
9. Histone deacetylase 4
General Function:
Zinc ion binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.
Gene Name:
HDAC4
Uniprot ID:
P56524
Molecular Weight:
119038.875 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>2000 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
10. Histone deacetylase 5
General Function:
Transcription factor binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.
Gene Name:
HDAC5
Uniprot ID:
Q9UQL6
Molecular Weight:
121976.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>2000 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
11. Histone deacetylase 6
General Function:
Zinc ion binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer.In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.
Gene Name:
HDAC6
Uniprot ID:
Q9UBN7
Molecular Weight:
131418.19 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>2000 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
12. Histone deacetylase 7
General Function:
Transcription corepressor activity
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565).
Gene Name:
HDAC7
Uniprot ID:
Q8WUI4
Molecular Weight:
102926.225 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>2000 uMNot AvailableBindingDB 50003616
References
  1. Fass DM, Shah R, Ghosh B, Hennig K, Norton S, Zhao WN, Reis SA, Klein PS, Mazitschek R, Maglathlin RL, Lewis TA, Haggarty SJ: Effect of Inhibiting Histone Deacetylase with Short-Chain Carboxylic Acids and Their Hydroxamic Acid Analogs on Vertebrate Development and Neuronal Chromatin. ACS Med Chem Lett. 2010 Oct 8;2(1):39-42. [21874153 ]
Target Details
13. NAD-dependent protein deacylase sirtuin-5, mitochondrial
General Function:
Zinc ion binding
Specific Function:
NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693). Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062). Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity). Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX.
Gene Name:
SIRT5
Uniprot ID:
Q9NXA8
Molecular Weight:
33880.605 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>100 uMNot AvailableBindingDB 50003616
References
  1. Madsen AS, Olsen CA: Substrates for efficient fluorometric screening employing the NAD-dependent sirtuin 5 lysine deacylase (KDAC) enzyme. J Med Chem. 2012 Jun 14;55(11):5582-90. doi: 10.1021/jm300526r. Epub 2012 May 24. [22583019 ]
Target Details
14. Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial
General Function:
Oxidoreductase activity, acting on the ch-ch group of donors, with a flavin as acceptor
Specific Function:
Has greatest activity toward short branched chain acyl-CoA derivative such as (s)-2-methylbutyryl-CoA, isobutyryl-CoA, and 2-methylhexanoyl-CoA as well as toward short straight chain acyl-CoAs such as butyryl-CoA and hexanoyl-CoA. Can use valproyl-CoA as substrate and may play a role in controlling the metabolic flux of valproic acid in the development of toxicity of this agent.
Gene Name:
ACADSB
Uniprot ID:
P45954
Molecular Weight:
47485.035 Da
References
  1. Ito M, Ikeda Y, Arnez JG, Finocchiaro G, Tanaka K: The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Biochim Biophys Acta. 1990 May 16;1034(2):213-8. [2112956 ]
15. Sodium channel protein (Protein Group)
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.
Included Proteins:
P35498 , Q9Y5Y9 , Q9UI33 , Q99250 , Q9NY46 , P35499 , Q14524 , Q01118 , Q9UQD0 , Q15858 , Q07699 , O60939 , Q9NY72 , Q8IWT1
References
  1. Farber NB, Jiang XP, Heinkel C, Nemmers B: Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(7):726-33. [12192617 ]
Target Details
16. Succinate-semialdehyde dehydrogenase, mitochondrial
General Function:
Succinate-semialdehyde dehydrogenase [nad(p)+] activity
Specific Function:
Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Gene Name:
ALDH5A1
Uniprot ID:
P51649
Molecular Weight:
57214.23 Da
References
  1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216. [12847559 ]
Target Details
17. Superoxide dismutase [Cu-Zn]
General Function:
Zinc ion binding
Specific Function:
Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name:
SOD1
Uniprot ID:
P00441
Molecular Weight:
15935.685 Da
References
  1. Plonka-Poltorak E, Zagrodzki P, Chlopicka J, Barton H, Westermarck T, Kaipainen P, Kaski M, Atroshi F: Valproic acid modulates superoxide dismutase, uric acid-independent FRAP and zinc in blood of adult epileptic patients. Biol Trace Elem Res. 2011 Dec;143(3):1424-34. doi: 10.1007/s12011-011-9003-3. Epub 2011 Mar 1. [21360059 ]
Target Details
18. Tissue factor
General Function:
Protease binding
Specific Function:
Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited protolysis. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade.
Gene Name:
F3
Uniprot ID:
P13726
Molecular Weight:
33067.3 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC501500 uMNot AvailableBindingDB 50003616
IC502000 uMNot AvailableBindingDB 50003616
References
  1. Wang J, Mahmud SA, Bitterman PB, Huo Y, Slungaard A: Histone deacetylase inhibitors suppress TF-kappaB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes. J Biol Chem. 2007 Sep 28;282(39):28408-18. Epub 2007 Aug 3. [17675290 ]
Target Details
19. UDP-glucuronosyltransferase 2B7
General Function:
Glucuronosyltransferase activity
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites. Is also active with androsterone, hyodeoxycholic acid and tetrachlorocatechol (in vitro).
Gene Name:
UGT2B7
Uniprot ID:
P16662
Molecular Weight:
60694.12 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1600 uMNot AvailableBindingDB 50003616
References
  1. Kiang TK, Ensom MH, Chang TK: UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005 Apr;106(1):97-132. Epub 2005 Jan 12. [15781124 ]
Target Details
20. Cellular tumor antigen p53
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
TP53
Uniprot ID:
P04637
Molecular Weight:
43652.79 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.76 uMAPR_p53Act_24h_upApredica
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 ]