| Title | Capture Compound Mass Spectrometry (CCMS) Sheds Light on the Molecular Mechanisms of Liver Toxicity of two Parkinson Drugs. | | Author(s) | Fischer JJ, Michaelis S, Schrey AK, Baessler O, Glinski M, Dreger M, Kroll F, Koester H | | Institution | caprotec bioanalytics GmbH, Volmerstrasse 5, 12489 Berlin, Germany. | | Source | Toxicol Sci 2009 Sep 26. | | Abstract | Capture Compound Mass Spectrometry (CCMS) is a novel technology that helps to understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: a selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyl transferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis for the difference of both drugs in respect to side effects. Using Capture Compounds with these drugs as selectivity functions we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone - protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off-targets. It fills a gap in currently used in-vitro screens for drug profiling that do not contain all of the toxicologically relevant proteins. Thereby CCMS has the potential to fill a technological need in drug safety assessment and helps to reengineer or to reject drugs at an early pre-clinical stage. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19783845 |
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