Valproic acid pathway (Homo sapiens)
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Description
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.
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- Li J, Norwood DL, Mao LF, Schulz H; ''Mitochondrial metabolism of valproic acid.''; Biochemistry, 1991 PubMed Europe PMC Scholia
- 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 PubMed Europe PMC Scholia
- 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 PubMed Europe PMC Scholia
- Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ; ''Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects.''; Clin Pharmacol Ther, 2008 PubMed Europe PMC Scholia
- Kiang TK, Ho PC, Anari MR, Tong V, Abbott FS, Chang TK; ''Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype.''; Toxicol Sci, 2006 PubMed Europe PMC Scholia
- Sadeque AJ, Fisher MB, Korzekwa KR, Gonzalez FJ, Rettie AE; ''Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid.''; J Pharmacol Exp Ther, 1997 PubMed Europe PMC Scholia
- Argikar UA, Remmel RP; ''Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10.''; Drug Metab Dispos, 2009 PubMed Europe PMC Scholia
- Kassahun K, Hu P, Grillo MP, Davis MR, Jin L, Baillie TA; ''Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes.''; Chem Biol Interact, 1994 PubMed Europe PMC Scholia
- Kassahun K, Farrell K, Abbott F; ''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.''; Drug Metab Dispos, 1991 PubMed Europe PMC Scholia
- ''''; , PubMed Europe PMC Scholia
- LuÃs PB, Ruiter JP, Ofman R, Ijlst L, Moedas M, Diogo L, Garcia P, de Almeida IT, Duran M, Wanders RJ, Silva MF; ''Valproic acid utilizes the isoleucine breakdown pathway for its complete β-oxidation.''; Biochem Pharmacol, 2011 PubMed Europe PMC Scholia
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| 2,3-diene-Valproic acid-CoA | Metabolite | HMDB60723 (HMDB)  | |
| 2-Propyl-2,4-pentadienoic acid | Metabolite | HMDB60682 (HMDB) | |
| 2-Propylglutaric acid | Metabolite | HMDB60684 (HMDB) | |
| 2-ene-Valproic acid CoA | Metabolite | HMDB60714 (HMDB) | |
| 2-n-Propyl-4-oxopentanoic acid | Metabolite | HMDB60683 (HMDB) | |
| 3-Hydroxyvalproic acid CoA | Metabolite | HMDB60744 (HMDB) | |
| 3-Hydroxyvalproic acid | Metabolite | HMDB13899 (HMDB) | |
| 3-Oxovalproic acid | Metabolite | HMDB60685 (HMDB) | |
| 3-ene-Valproic acid CoA | Metabolite | HMDB60740 (HMDB) | |
| 3-oxo-Valproic acid CoA | Metabolite | HMDB60749 (HMDB) | |
| 4-Hydroxyvalproic acid | Metabolite | HMDB13900 (HMDB) | |
| 4-ene-Valproic acid CoA | Metabolite | HMDB60762 (HMDB) | |
| 4-ene-Valproic acid | Metabolite | HMDB13897 (HMDB) | |
| 5-Hydroxyvalproic acid | Metabolite | HMDB13898 (HMDB) | |
| ABAT | GeneProduct | ENSG00000183044 (Ensembl) | |
| ACADSB | GeneProduct | ENSG00000196177 (Ensembl) | |
| ACSM1 | GeneProduct | ENSG00000166743 (Ensembl) | |
| CYP2A6 | GeneProduct | ENSG00000255974 (Ensembl) | |
| CYP2B6 | GeneProduct | ENSG00000197408 (Ensembl) | |
| CYP2C9 | GeneProduct | ENSG00000138109 (Ensembl) | |
| EHHADH | GeneProduct | ENSG00000113790 (Ensembl) | |
| GABA | Metabolite | HMDB00112 (HMDB) | |
| HADHA | GeneProduct | ENSG00000084754 (Ensembl) | |
| HADHB | GeneProduct | ENSG00000138029 (Ensembl) | |
| HDAC1 | GeneProduct | ENSG00000116478 (Ensembl) | |
| HSD17B10 | GeneProduct | ENSG00000072506 (Ensembl) | |
| IVD | GeneProduct | ENSG00000128928 (Ensembl) | |
| Pentanoyl-CoA | Metabolite | HMDB13037 (HMDB) | |
| Propionyl-CoA | Metabolite | HMDB01275 (HMDB) | |
| UGT1A3 | GeneProduct | ENSG00000243135 (Ensembl) | |
| Uridine 5'-diphosphate | Metabolite | HMDB00295 (HMDB) | |
| Uridine diphosphate glucuronic acid | Metabolite | HMDB00935 (HMDB) | |
| Valproic acid CoA | Metabolite | HMDB60877 (HMDB) | |
| Valproic acid glucuronide | Metabolite | HMDB00901 (HMDB) | |
| Valproic acid | Metabolite | HMDB01877 (HMDB) |
Annotated Interactions
No annotated interactions
