Mitochondrial toxicity (Glu/Gal) assay

• Impairment of mitochondrial function is increasingly implicated in the etiology of drug-induced toxicity. For example, mitochondrial dysfunction was found to play a role in the toxicity of troglitazone and cerivastatin which were withdrawn from the US market in 2000 and 2001 respectively.¹
• Mitochondria produce >90% of the cellular energy requirements in the form of adenosine triphosphate (ATP) via oxidative phosphorylation.
• Many cell lines developed for use in vitro are metabolically adapted for growth under hypoxic and anaerobic conditions using high glucose media and derive most of their energy from glycolysis rather than mitochondrial oxidative phosphorylation (a process termed the Crabtree effect). This reduces the cells susceptibility to mitochondrial toxicants.²
• Circumventing the Crabtree effect by replacing glucose with galactose in the cell media increases the reliance of the cells on mitochondrial oxidative phosphorylation to obtain ATP. By comparing the toxic effects of different drugs in the glucose and galactose media, it is possible to detect mitochondrial impairment and identify if this is a primary effect or secondary to other cytotoxic mechanisms.²
• Cyprotex evaluates mitochondrial toxicity using HepG2 cells, U-87 MG cells or other cell lines (available on request).

Clinical signs of drug induced mitochondrial impairment range from obvious and severe to more subtle reflections of modest loss of mitochondrial capacity such as exercise intolerance, malaise, and mild lactic acidosis.

¹Dykens JA and Will Y (2007) Drug Discovery Today 12; 777-785