Drug Toxicity and Mitochondria
The following is an excerpt from a brochure for test kits to measure mitochondrial toxicity during drug trials:
"There is an increasing emphasis on reducing attrition through the preclinical and clinical phases of drug development in order to minimize the number of drugs withdrawn from the market, or having their use curtailed by warnings due to adverse effects. This is often because the adverse effect is subtle and does not necessarily lead to histopathology. Among the drugs that have been withdrawn in recent years, several have since been shown to cause serious impairment to mitochondrial function, including cerivastatin (Baycol), troglitazone (Rezulin), nefazodone (Serzone) and tolcapone (Tasmar) . Not surprisingly, there is now much more focus on identifying mitochondrial toxicity early in the development process. Early indicators of mitochondrial toxicity from one or more of these effects are:
• Altered intracellular ATP levels
• Increased intracellular reactive oxygen species (ROS)
• Reduced mtDNA-encoded protein expression
• Increased extracellular acidification
• Altered oxygen consumption
• Reduced membrane potential"
Drugs in General:
Table of Reported Drugs with Mitochondrial Toxicity from MitoAction
Fundam Clin Pharmacol. 2008 Aug;22(4):335-53
Drug-associated mitochondrial toxicity and its detection.
Drug-induced mitochondrial dysfunction in cardiac and skeletal muscle injury
Expert Opin Drug Saf. 2008 Mar;7(2):129-46
Differentiating Mitochondrial Toxicity from Other Types of Mechanistic Toxicity
In spite of the critical roles that mitochondria play in all cells and the many ways they can be adversely affected by chemical compounds, mitochondrial toxicity is difficult to identify. Many of the cell lines used in high-throughput drug discovery screens are highly proliferative, immortalized cell lines that, in the presence of glucose, use glycolysis for energy production, despite abundant oxygen and functional mitochondria, a phenomenon known as the Crabtree effect . As a result these cells tend to be resistant to compounds that disrupt mitochondrial oxidative respiration . In addition, almost all cells can tolerate diminished mitochondrial membrane potential as long as minimal capacity is maintained; however, when that minimal capacity is lost, cells die rapidly via apoptosis or necrosis, and mitochondrial toxicity is not often identified as the underlying cause of cell death . Often with mitochondrial toxicity there is a lack of correlation between drug dose and toxicity, and toxicity can be missed in clinical trials because it is often highly dependent on individual genetics and organ history ."
Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients
J Young Pharm. 2011 Oct-Dec; 3(4): 304–309.
Apoptosis. 2012 May;17(5):516-27
Biochim Biophys Acta. 1989 Apr 25;991(1):68-78.
"Micromolar quantities of aluminum have been found (Dill et al. (1987) J. Membrane Biol. 99, 187-196) to reduce the voltage dependence of the mitochondrial outer membrane channel, VDAC, from Neurospora crassa. In the present study, various metallic and organic ions were tested for possible aluminum-like effect, and only the trivalent metals exhibited a similar ability to reduce the channels voltage dependence... While providing new insight into the nature of VDAC's sensor, these results also indicate that aluminum-cell interaction may result from the presence of AI(OH)3 in solution in addition to the widely accepted AI3+-mediated interactions. While the [AI3+] is vanishingly low at neutral pH, the trihydroxide is the major form and should be considered as an important candidate for aluminum-induced cellular effects."
Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review.
Role of metals in neuronal apoptosis: challenges associated with neurodegeneration.
Mitochondria as a Target of Environmental Toxicants
Toxicol. Sci. (2013) First published online: April 29, 2013
Science Daily February 20, 2015
Acute ethanol administration oxidatively damages and depletes mitochondrial DNA in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants.
Viruses as Modulators of Mitochondrial Functions