Chlorpromazine
From ToxBankWiki
Executive Summary
Compound | Chlorpromazine |
Toxicities | Cholestasis, cytotoxicity. |
Mechanisms | Chlorpromazine is activated by oxidation to electrophilic species that disrupt mitochondrial function and form adducts with cellular thiols. However, comparable toxicity is observed for both the parent compound and its reactive metabolite(s). The parent compound is classified as a promiscuous ligand that inserts into phospholipid membranes and modulates the activity of multiple membrane-bound proteins, for example complex V of the oxidative phosphorylation chain. |
Comments | This compound was selected to test the ability of cell-based assays to detect cholangiopathies that result from disruption of bile ducts. |
Feedback Contact | Gold Compound Working Group (GCWG) |
Chlorpromazine | |
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Identifiers | |
Leadscope Id | LS-105361 |
CAS | 50-53-3 |
DrugBank | DB00477 |
ChemSpider | 2625 |
UNII | U42B7VYA4P |
Pathway DBs | |
KEGG | D00270 |
Assay DBs | |
PubChem CID | 2726 |
ChEMBL | 71 |
Omics DBs | |
Open TG-Gate | 00016 |
Properties | |
pKa | 8.86 |
ToxCast Accepted | yes |
Toxic Effect | Steatosis |
ToxBank Accepted | yes |
Approved on | 2011-06-28 |
Target | dopamine, serotonin, adrenergic, histamine receptors |
Toxicities | Cholestasis,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 | 31.9205 | hepato-lenticular degeneration |
2 | 4.71378 | liver injury |
2 | 9.14854 | vanishing bile duct 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 "Chlorpromazine" as an active ingredient.
FDA Label Search
PubMed references
The following resource link will perform a PubMed query for the terms "Chlorpromazine" and "liver toxicity".
Chlorpromazine 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 | |||||||||||||||||||||
References | |||||||||||||||||||||
+ | + | + | + | 2 |
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] |
References
- ↑ Cullen, J.M., 2005. Mechanistic classification of liver injury. Toxicol. Pathol. 33, 6–8.
- ↑ Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
- ↑ Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
- ↑ Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
- ↑ Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
- ↑ Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
- ↑ Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
- ↑ Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
- ↑ Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
- ↑ Chatman, L.A., Morton, D., Johnson, T.O., Anway, S.D., 2009. A strategy for risk management of drug-induced phospholipidosis. Toxicol. Pathol. 37, 997–1005.
- ↑ Halliwell, W.H., 1997. Cationic amphiphilic drug-induced phospholipidosis. Toxicol. Pathol. 25, 53–60.
- ↑ Kasahara, T., Tomita, K., Murano, H., Harada, T., Tsubakimoto, K., Ogihara, T., Ohnishi, S., Kakinuma, C., 2006. Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential. Toxicol. Sci. 90, 133–141.
- ↑ Nioi, P., Perry, B.K., Wang, E.J., Gu, Y.Z., Snyder, R.D., 2007. In vitro detection of druginduced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol. Sci. 99, 162–173.
- ↑ Nonoyama, T., Fukuda, R., 2008. Drug-induced phospholipidosis – pathological aspects and its prediction. J. Toxicol. Pathol. 21, 9–34.
- ↑ Pappu, A., Hostetler, K.Y., 1984. Effect of cationic amphiphilic drugs on the hydrolysis of acidic and neutral phospholipids by liver lysosomal phospholipase A. Biochem. Pharmacol. 33, 1639–1644.
- ↑ Reasor, M.J., Hastings, K.L., Ulrich, R.G., 2006. Drug-induced phospholipidosis: issues and future directions. Expert Opin. Drug Saf. 5, 567–583.
- ↑ Reasor, M.J., Kacew, S., 2001. Drug-induced phospholipidosis: are there functional consequences? Exp. Biol. Med. (Maywood) 226, 825–830.
- ↑ Sawada, H., Takami, K., Asahi, S., 2005. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83, 282–292.
- ↑ 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.
- ↑ Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
- ↑ Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
- ↑ Marion, T.L., Leslie, E.M., Brouwer, K.L., 2007. Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol. Pharm. 4, 911–918.
- ↑ Palmeira, C.M., Rolo, A.P., 2004. Mitochondrially-mediated toxicity of bile acids. Toxicology 203, 1–15.
- ↑ Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
- ↑ Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
- ↑ Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
- ↑ Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
- ↑ Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
- ↑ Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
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Calculated/Predicted Properties
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The recommended source is Sigma Aldrich, product number 31679.
Chlorpromazine | |
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Source | Sigma Aldrich |
Product ID | 31679 |
Mol Weight | Chlorpromazine hydrochloride 355.33 |
Purity | >99.9 % |
Brand | VETRANAL |
Quantity | 250 mg |
Cost | 26.8 |
Comment | The purity is not specified on the website and refers to the certificate of analysis of the batch available in October 2011. |
Storage | Store at +4 °C |
Stability | Not stable in aqueous solution. We strongly recommend always to use freshly prepared solutions.Protect from light.(Enzo Lifescience Product n. ALX-270-171) |