Review
Post ScreenThe significance of mitochondrial toxicity testing in drug development
Post Screen
Section snippets
Attrition of drugs causes humanitarian and financial losses
Of the new drugs approved by the US Food and Drug Administration (FDA) between 1994 and 2006, 38 were later withdrawn from the market because of safety concerns, the majority being hepatotoxic and cardiotoxic (Figure 1) [1]. Although this represents only 2–3% of the total, such failures to predict adverse drug reactions result in unacceptable human suffering, erode trust in the regulatory process and pharmaceutical industry, and impose immense financial losses.
A decade ago, 40% of
Function of normal mitochondria
The dominant function of mitochondria is the production of >90% of the cell's energy in form of adenosine triphosphate (ATP). This double-membraned organelle contains its own DNA (mitochondrial, or mtDNA) with a genetic code that differs from that in nuclear DNA. Mitochondria also contain the requisite mechanisms to replicate and express their genome. Mitochondria replicate independently of cell division with a typical half-life of five days to several weeks depending on the tissue. Although
Drug-induced mitochondrial toxicity
Mitochondrial replication requires the capacity to replicate and express mtDNA, and mitochondrial function depends predominantly on the impermeability of the inner membrane and the catalytic integrity of the respiratory complexes. It was not until the launch of NRTIs (nucleotide reverse transcriptase inhibitors) that mitochondrial toxicity was widely accepted as causing organ toxicities. Many NRTI's inhibit the polymerase that replicates mtDNA, thereby preventing mitochondrial replication. This
Clinical presentation of drug-induced mitochondrial toxicity
Mitochondrial impairment typically affects the most aerobically poised tissues, such as kidney and heart, or tissues exposed to higher concentrations of the drug, such as the liver, because of hepatoportal absorption of oral drugs and robust capacity for bioactivation. Similarly, bio-accumulation of statins by fast twitch skeletal muscle cells puts this fiber type at particular risk of mitochondrially induced rhabdomyolysis [38].
As mitochondrial function declines, cells respond to the loss of
Pre-clinical detection of drug-induced mitochondrial toxicity
Appreciation of the importance of drug-induced mitochondrial toxicity has recently accelerated, fostered by the development of techniques conducive to drug-development efforts. For example, the vast majority of immortalized cell lines used to evaluate drug toxicity pre-clinically are derived from cancers and are typically grown under culture conditions of supraphysiological glucose concentrations 42, 43. However, despite the presence of metabolically competent mitochondria, cells grown under
Mitochondrial testing in drug development
In order to increase drug safety and reduce attrition rates, pharmaceutical companies have started to explore and adopt newer in vivo, in vitro, and in silico tools, as well as new technologies such as the ‘omics’ platforms [72]. In addition, many limited duration teams and consortia have been formed to tackle specific issues such as hepatotoxicity, carcinogenicity, and vasculitis [http://www.fda.gov/bbs/topics/news/2006/NEW01337.html, http://rarediseasesnetwork.epi.usf.edu].
In large
References (100)
Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells
Toxicol. Lett.
(2005)Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones
Toxicology
(2006)Bcl-xL overexpression protects from apoptosis induced by HMG-CoA reductase inhibitors in murine tubular cells
Kidney Int.
(2003)Entacapone, a novel catechol-O-methyltransferase inhibitor for Parkinson's disease, does not impair mitochondrial energy production
Eur. J. Pharmacol.
(1997)Effects of entacapone and tolcapone on mitochondrial membrane potential
Eur. J. Pharmacol.
(2002)The physiological regulation of uncoupling proteins
Biochim. Biophys. Acta
(2006)Statins induce calcium-dependent mitochondrial permeability transition
Toxicology
(2006)Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy
Lancet
(1991)Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays
Toxicol. In Vitro
(2007)Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver
Hepatology
(2002)