**Author details**

**Hepatic Toxicity Renal Toxicity Cardiovascular Toxicity**





inhibitors (NRTIs) - Meloxicam - Pioglitazone - Sulindac



**Table 2.** Examples of Drugs with Black Box Warnings for Mitochondrial Toxicity

have been pushed forward for further clinical trials.

Refining of the different methodologies results into higher achievement in the isolation of functional mitochondria from different organs, which can be used in further mechanistic studies to identify tissue-specific drug-induced mitochondrial toxicity. Nevertheless, studies with isolated mitochondria lack the complexity associated with experiments in intact cells, isolated organs or even in vivo studies. But the use of isolated mitochondrial fractions helps determining precise sites of action of the molecule on mitochondria. If everything works OK, the accurate drug safety assessment would correlate data in isolated mitochondria with data collected in intact cells and *in vivo* (figure 3).One important issue in this discussion includes what can be gained by using mitochondria as a biosensor to search drug safety. One particular example was nefazodone, an anti-depressant. This drug was withdrawn from the market in 2004, following several clinical reports of serious liver toxicity [35]. Would the use of mito‐ chondria as cost effective accelerated biosensors of drug safety helped in avoiding the entry of the drug in the market? The answer is, maybe so. Dykens*et al.* demonstrated that nefazodone is highly toxic to isolated liver mitochondria, human hepatocytes and HepG2 cells, showing an obvious cytotoxicity even when cell lines were used. [36] If an initial assessment of mitochondrial toxicity for nefazodone had been done, it is very unlikely that the drug would

**-** Metformin - Valproic acid - Ketoconazole - Isoniazid - Nefazodone - Lamivudine - Divalproex Sodium

78 Toxicology Studies - Cells, Drugs and Environment


> Jalal Pourahmad\* , Ahmad Salimi and Enayatollah Seydi

Running Title

22 23

\*Address all correspondence to: j.pourahmadjaktaji@utoronto.ca

Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
