Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays.


Nadanaciva, Sashi; Bernal, Autumn; Aggeler, Robert; Capaldi, Roderick; Will, Yvonne

Publication Year 2007
Journal Toxicology in Vitro
Pages 902-911
Volume 21
Issue 5
PMID 17346924.0
DOI 10.1016/j.tiv.2007.01.011

Mitochondrial dysfunction has been shown to be a pharmacotoxicological response to a variety of currently-marketed drugs. In order to reduce attrition due to mitochondrial toxicity, high throughput-applicable screens are needed for early stage drug discovery. We describe, here, a set of immunocapture based assays to identify compounds that directly inhibit four of the oxidative phosphorylation (OXPHOS) complexes: I, II, IV, and V. Intra- and inter-assay variation were determined and specificity tested by using classical mitochondrial inhibitors. Twenty drugs, some with known mitochondrial toxicity and others with no known mitochondrial liability, were studied. Direct inhibition of one or more of the OXPHOS complexes was identified for many of the drugs. Novel information was obtained for several drugs including ones with previously unknown effects on oxidative phosphorylation. A major advantage of the immunocapture approach is that it can be used throughout drug screening from early compound evaluation to clinical trials.