Valproic Acid
From ToxBankWiki
Executive Summary Information
Compound | Valproic Acid |
Toxicities | Steatosis, cytotoxicity |
Mechanisms | As a fatty acid analogue, the compound is a competitive inhibitor of fatty acid metabolism, which accounts for steatosis. The parent compound is also hepatotoxic by a mechanism that has not been resolved; however, this hydrophobic compound is used at very high concentrations and its promiscuous activity at these concentrations is likely due to disruption of membrane integrity. P450 ω-oxidation produces a reactive alkylating and free radical-propagating agent that adds to the toxicity profile. |
Comments | This compound was selected as a reference standard for steatosis via inhibition of β-oxidation. |
Feedback Contact | Gold Compound Working Group (GCWG) |
Valproic Acid | |
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Identifiers | |
Leadscope Id | LS-2068 |
CAS | 99-66-1 |
DrugBank | DB00313 |
ChemSpider | 3009 |
UNII | 614OI1Z5VM |
Pathway DBs | |
KEGG | D00399 |
Assay DBs | |
PubChem CID | 3121 |
ChEMBL | 109 |
Omics DBs | |
Open TG-Gate | 00005 |
Properties | |
pKa | 4.72 |
ToxCast Accepted | yes |
Toxic Effect | Steatosis |
ToxBank Accepted | yes |
Approved on | 2011-06-28 |
Target | GABA transaminase |
Toxicities | Cytotoxicity |
- In Vivo Data
- LIINTOP Data
- PK-ADME Data
- 'Omics and IC50 Data
- Physical Properties
- Recommended Product and Source
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Human Adverse Events
The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.
# Reports | Report:Baseline Ratio | Adverse Event |
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1 | 38.1785 | gallbladder anomaly congenital |
2 | 4.64781 | hepatic adenoma |
1 | 7.42359 | hepatitis neonatal |
9 | 3.75233 | hepatocellular injury |
259 | 41.4725 | hyperammonaemia |
3 | 10.1487 | mixed liver injury |
7 | 9.40073 | reye's syndrome |
FDA and Label Information
The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products
This next url will perform a search in the FDA's system for all labels for products that contain "Valproic acid" as an active ingredient.
FDA Label Search
PubMed references
The following resource link will perform a PubMed query for the terms "Valproic acid" and "liver toxicity".
Valproic acid Search
The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.
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Summary Hepatotoxic Effects from the LIINTOP FP6 Program | |||||||||||||||||||||
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+ | + | + | + | + | + | 3 |
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] |
References
- ↑ Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
- ↑ Ioannides, C., Lewis, D.F., 2004. Cytochromes P450 in the bioactivation of chemicals. Curr. Top. Med. Chem. 4, 1767–1788.
- ↑ Kang, P., Dalvie, D., Smith, E., Zhou, S., Deese, A., Nieman, J.A., 2008. Bioactivation of flutamide metabolites by human liver microsomes. Drug Metab. Dispos. 36, 1425–1437.
- ↑ Li, A.P., 2002. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘‘multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact. 142, 7–23.
- ↑ Park, K., Williams, D.P., Naisbitt, D.J., Kitteringham, N.R., Pirmohamed, M., 2005b. Investigation of toxic metabolites during drug development. Toxicol. Appl. Pharmacol. 207, 425–434.
- ↑ Reddy, M.V., Storer, R.D., Laws, G.M., Armstrong, M.J., Barnum, J.E., Gara, J.P., McKnight, C.G., Skopek, T.R., Sina, J.F., DeLuca, J.G., Galloway, S.M., 2002. Genotoxicity of naturally occurring indolecompounds: correlation between covalentDNAbinding and other genotoxicity tests. Environ. Mol. Mutagen. 40, 1–17.
- ↑ Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
- ↑ Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
- ↑ Jones, D.P., Lemasters, J.J., Han, D., Boelsterli, U.A., Kaplowitz, N., 2010. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol. Interv. 10, 98–111.
- ↑ Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
- ↑ Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
- ↑ Bradbury, M.W., Berk, P.D., 2004. Lipid metabolism in hepatic steatosis. Clin. Liver Dis. 8, 639–671 (xi).
- ↑ Chariot, P., Drogou, I., de Lacroix-Szmania, I., Eliezer-Vanerot, M.C., Chazaud, B., Lombes, A., Schaeffer, A., Zafrani, E.S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30, 156–160.
- ↑ Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
- ↑ Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
- ↑ Fromenty, B., Pessayre, D., 1997. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J. Hepatol. 26 (Suppl. 2), 43–53.
- ↑ Letteron, P., Sutton, A., Mansouri, A., Fromenty, B., Pessayre, D., 2003. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38, 133–140.
- ↑ Shokolenko, I., Venediktova, N., Bochkareva, A., Wilson, G.L., Alexeyev, M.F., 2009. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res. 37, 2539–2548.
- ↑ Criddle, D.N., Gillies, S., Baumgartner-Wilson, H.K., Jaffar, M., Chinje, E.C., Passmore, S., Chvanov, M., Barrow, S., Gerasimenko, O.V., Tepikin, A.V., Sutton, R., Petersen, O.H., 2006. Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J. Biol. Chem. 281, 40485–40492.
- ↑ Hanley, P.J., Ray, J., Brandt, U., Daut, J., 2002. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J. Physiol. 544, 687–693.
- ↑ Moridani, M.Y., Cheon, S.S., Khan, S., O’Brien, P.J., 2003. Metabolic activation of 3- hydroxyanisole by isolated rat hepatocytes. Chem. Biol. Interact. 142, 317–333.
- ↑ Pereira, C.V., Moreira, A.C., Pereira, S.P., Machado, N.G., Carvalho, F.S., Sardao, V.A., Oliveira, P.J., 2009. Investigating drug-induced mitochondrial toxicity: a biosensor to increase drug safety? Curr. Drug Saf. 4, 34–54.
- ↑ Sanz, A., Caro, P., Gomez, J., Barja, G., 2006. Testing the vicious cycle theory of mitochondrial ROS production: effects of H2O2 and cumene hydroperoxide treatment on heart mitochondria. J. Bioenerg. Biomembr. 38, 121–127.
- ↑ Yuan, L., Kaplowitz, N., 2009. Glutathione in liver diseases and hepatotoxicity. Mol. Aspects Med. 30, 29–41.
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Calculated/Predicted Properties
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