Valproic acid pathway (WP3871)
Homo sapiens
Valproic acid is a drug used for 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. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract and then binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. It is also a histone deacetylase inhibitor. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection. Source: description from http://www.drugbank.ca/drugs/DB00313 Metabolic pathway from: http://smpdb.ca/view/SMP00635 Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3871 CPTAC Assay Portal].
Authors
Friederike Ehrhart , Denise Slenter , and Kristina HanspersActivity
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Organisms
Homo sapiensCommunities
DiseasesAnnotations
Disease Ontology
epilepsyPathway Ontology
xenobiotic metabolic pathway valproic acid drug pathwayCell Type Ontology
neuron hepatocyte| Label | Type | Compact URI | Comment |
|---|---|---|---|
| GABA | Metabolite | hmdb:HMDB0000112 | |
| Pentanoyl-CoA | Metabolite | hmdb:HMDB0013037 | |
| 3-Oxovalproic acid | Metabolite | hmdb:HMDB0060685 | |
| 2-Propylglutaric acid | Metabolite | hmdb:HMDB0060684 | |
| 3-Hydroxyvalproic acid | Metabolite | hmdb:HMDB0013899 | |
| 2-Propyl-2,4-pentadienoic acid | Metabolite | hmdb:HMDB0060682 | |
| 3-ene-Valproic acid CoA | Metabolite | hmdb:HMDB0060740 | |
| 4-ene-Valproic acid | Metabolite | hmdb:HMDB0013897 | |
| 2-n-Propyl-4-oxopentanoic acid | Metabolite | hmdb:HMDB0060683 | |
| 4-ene-Valproic acid CoA | Metabolite | hmdb:HMDB0060762 | |
| 2,3-diene-Valproic acid-CoA | Metabolite | hmdb:HMDB0060723 | |
| Propionyl-CoA | Metabolite | hmdb:HMDB0001275 | |
| 4-Hydroxyvalproic acid | Metabolite | hmdb:HMDB0013900 | |
| 2,3-diene-Valproic acid-CoA | Metabolite | hmdb:HMDB0060723 | |
| 3-ene-Valproic acid CoA | Metabolite | hmdb:HMDB0060740 | |
| Uridine 5'-diphosphate | Metabolite | hmdb:HMDB0000295 | |
| 3-Hydroxyvalproic acid CoA | Metabolite | hmdb:HMDB0060744 | |
| 3-oxo-Valproic acid CoA | Metabolite | hmdb:HMDB0060749 | |
| Valproic acid CoA | Metabolite | hmdb:HMDB0060877 | |
| 2-ene-Valproic acid CoA | Metabolite | hmdb:HMDB0060714 | |
| 5-Hydroxyvalproic acid | Metabolite | hmdb:HMDB0013898 | |
| Valproic acid | Metabolite | hmdb:HMDB0001877 | |
| Uridine diphosphate glucuronic acid | Metabolite | hmdb:HMDB0000935 | |
| Valproic acid glucuronide | Metabolite | hmdb:HMDB0000901 | |
| ACSM1 | GeneProduct | ensembl:ENSG00000166743 | |
| HADHB | GeneProduct | ensembl:ENSG00000138029 | |
| UGT1A3 | GeneProduct | ensembl:ENSG00000243135 | |
| EHHADH | GeneProduct | ensembl:ENSG00000113790 | |
| CYP2B6 | GeneProduct | ensembl:ENSG00000197408 | |
| HDAC1 | GeneProduct | ensembl:ENSG00000116478 | |
| HSD17B10 | GeneProduct | ensembl:ENSG00000072506 | |
| HADHA | GeneProduct | ensembl:ENSG00000084754 | |
| CYP2A6 | GeneProduct | ensembl:ENSG00000255974 | |
| CYP2C9 | GeneProduct | ensembl:ENSG00000138109 | |
| ACADSB | GeneProduct | ensembl:ENSG00000196177 | |
| IVD | GeneProduct | ensembl:ENSG00000128928 | |
| ABAT | GeneProduct | ensembl:ENSG00000183044 | |
| ACADSB | GeneProduct | ensembl:ENSG00000196177 | |
| CYP2A6 | GeneProduct | ensembl:ENSG00000255974 | |
| CYP2B6 | GeneProduct | ensembl:ENSG00000197408 | |
| CYP2C9 | GeneProduct | ensembl:ENSG00000138109 | |
| CYP2A6 | GeneProduct | ensembl:ENSG00000255974 |
References
- Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans. Kassahun K, Farrell K, Abbott F. Drug Metab Dispos. 1991;19(2):525–35. PubMed Europe PMC Scholia
- Mitochondrial metabolism of valproic acid. Li J, Norwood DL, Mao LF, Schulz H. Biochemistry. 1991 Jan 15;30(2):388–94. PubMed Europe PMC Scholia
- The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Ito M, Ikeda Y, Arnez JG, Finocchiaro G, Tanaka K. Biochim Biophys Acta. 1990 May 16;1034(2):213–8. PubMed Europe PMC Scholia
- Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes. Kassahun K, Hu P, Grillo MP, Davis MR, Jin L, Baillie TA. Chem Biol Interact. 1994 Mar;90(3):253–75. PubMed Europe PMC Scholia
- Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. Sadeque AJ, Fisher MB, Korzekwa KR, Gonzalez FJ, Rettie AE. J Pharmacol Exp Ther. 1997 Nov;283(2):698–703. PubMed Europe PMC Scholia
- Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Ho PC, Abbott FS, Zanger UM, Chang TKH. Pharmacogenomics J. 2003;3(6):335–42. PubMed Europe PMC Scholia
- UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, et al. J Pharmacol Exp Ther. 2005 Jun;313(3):1340–6. PubMed Europe PMC Scholia
- Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Kiang TKL, Ho PC, Anari MR, Tong V, Abbott FS, Chang TKH. Toxicol Sci. 2006 Dec;94(2):261–71. PubMed Europe PMC Scholia
- Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, et al. Clin Pharmacol Ther. 2008 Apr;83(4):595–600. PubMed Europe PMC Scholia
- Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Argikar UA, Remmel RP. Drug Metab Dispos. 2009 Jan;37(1):229–36. PubMed Europe PMC Scholia
- Valproic acid utilizes the isoleucine breakdown pathway for its complete β-oxidation. Luís PBM, Ruiter JP, Ofman R, Ijlst L, Moedas M, Diogo L, et al. Biochem Pharmacol. 2011 Dec 1;82(11):1740–6. PubMed Europe PMC Scholia