|Toxicities||Gastric ulcers on chronic use. Salicylate intoxication with acute overdoses.|
|Mechanisms||Both the native drug and salicylic acid hydrolysis product are implicated in toxicity. Hepatotoxicity is extremely rare compared to the 10, 000 tons of aspirin consumed annually. Mechanisms of toxicity are not fully understood and toxicity in cell culture is observed at very high – 10 mM – concentrations, implying the possibility of multiple non-specific cellular toxicities.|
|Comments||Given the very high concentrations required, rare observation of toxicity, and the lack of a clear understanding of mechanisms, ‘omics profiles for this compound will be difficult to interpret in a predictive sense.|
|Recommended as Standard||No|
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.
|Summary Hepatotoxic Effects from the LIINTOP FP6 Program|
Gold Compound Evaluation and Comments
The following table is organized into four main sections and provides a detailed assessment by the Gold Compound Working Group for the use of this compound as a standard hepatotoxin. The table's four sections (collapsed by default but will expand when the "show" link is clicked) contains detailed information for the core set of SEURAT compound acceptance criteria.
|Standard to Meet||Compound Assessment|
Proprietary Toxicity Literature Report
The toxicity literature report contains proprietary information and references for studies performed on this compound relevant to liver toxicity findings and is restricted for use within the SEURAT program only.
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|
|3||6.42937||cholestatic liver injury|
|2||132.874||hepatic cyst ruptured|
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 "Acetylsalicylic acid/Aspirin" as an active ingredient.
FDA Label Search
The following resource link will perform a PubMed query for the terms "Acetylsalicylic acid" and "liver toxicity".
Acetylsalicylic acid Search
- ↑ 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.
- ↑ Toxicity should be observed clinically with higher frequency at higher doses. If toxicity is idiosyncratic due to defects in metabolism that result in higher than normal exposure, then this toxicity is still considered to fit our definition of dose-dependent toxicity. If toxicity is idiosyncratic due to an increased sensitivity of the organ to the toxin - due to disease, genetics, or co-administered drug, for example - then this toxicity is outside our area of interest.
- ↑ The in vivo therapeutic window is used to estimate an appropriate concentration for in vitro toxicity assays. This in vitro concentration should also be consistent with the exposure implied by pharmacokinetics parameters.
- ↑ 21.0 21.1 We prefer compounds that require metabolic activation, although standards that are active in themselves will be accepted if they have otherwise valuable properties. We require knowing the active metabolite, and we prefer compounds where the metabolite is stable and can be independently tested in order to verify the mechanism of toxicity as well as of metabolic activation in the test cell line.
- ↑ Literature data for at least one, but not necessarily all, of the ‘omics datasets is desired. This requirement can be waived in special cases.
- ↑ 23.0 23.1 23.2 23.3 23.4 The IC50’s for in vitro efficacy and toxicity should be consistent with the therapeutic ratio observed in the clinic. These parameters will be dependent on specific cell type and culture conditions, but differences of more than 30-fold in the in vitro vs. in vivo therapeutic ratios should be considered suspect and carefully justified.
- ↑ This is not a equirement, but compounds utilized in the EPA testing program can be assumed to have physical properties verified to be suitable for in vitro cellular assays.
- ↑ Sparing soluble compounds may be assayed for solubility in serum and the percent serum used specified here.
- ↑ This property will be measured when a sample of compound becomes available.
|Accepted by ToxBank||no +|
|Accepted by ToxCast||yes +|
|Equivalent URIThis property is a special property in this wiki.||http://bio2rdf.org/drugbank_drugs:DB00945 +, http://bio2rdf.org/cas:50-78-2 +, http://www.chemspider.com/Chemical-Structure.2157.rdf +, http://bio2rdf.org/pubchem:2244 +, http://bio2rdf.org/dr:D00109 +, and http://bio2rdf.org/chebi:15365 +|
|Has CAS||50-78-2 +|
|Has ChEBI Id||15365 +|
|Has ChEMBL Id||25 +|
|Has ChemSpider Id||2157 +|
|Has DrugBank Id||DB00945 +|
|Has KEGG Id||D00109 +|
|Has Leadscope Id||LS-143 +|
|Has Open-TG-Gate Id||00014 +|
|Has PubChem CID||2244 +|
|Has Smiles||CC(=O)OC1=CC=CC=C1C(=O)O +|
|Has category||Hepatotoxic +|
|Has image||Acetylsalicylic_acid.png +|
|Has pKa||3.63 +|
|Has target||COX-1, COX-2 +|
|Has toxic effect||Steatosis +|