Can drug safety be predicted and animal experiments reduced by using isolated mitochondrial fractions?
Mitochondrial toxicity has resulted in the withdrawal of several drugs from the market. One particular example is nefazodone, an anti-depressant withdrawn in the USA due to hepatoxicity caused by drug-induced mitochondrial dysfunction. Drug development and safety testing can involve the use of large numbers of laboratory animals, which, without a decisive pre-screening for mitochondrial toxicity, are often unable to pre-empt higher mortality rates in some patient groups. The use of isolated mitochondria as a screening tool for drug safety can decrease the number of laboratory animals used in pre-clinical studies, thus improving animal welfare and healthcare outcomes and costs. Novel techniques involving high-throughput methods can be used to investigate whether a molecule is a mitochondrial toxicant. Moreover, these screens are mechanistically-based, since the effects of the drug on oxidative phosphorylation, calcium homeostasis and mitochondrial genetics can be assessed. This review is intended to demonstrate that isolated mitochondrial fractions are suitable for predicting drug and general chemical safety in toxicological screenings, thus contributing to the refinement and reduction of animal use in laboratory research.
Pereira
Susana P
SP
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, Portugal.
Pereira
Gonçalo C
GC
Moreno
António J
AJ
Oliveira
Paulo J
PJ
D000826:Animal Testing Alternatives; D000818:Animals; D000830:Animals, Laboratory; D002458:Cell Fractionation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000503:physiopathology; D057166:High-Throughput Screening Assays; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D023421:Models, Animal; D010539:Permeability / Q000187:drug effects; D011237:Predictive Value of Tests; D018570:Risk Assessment; D015262:Xenobiotics / Q000633:toxicity*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015262:Xenobiotics