Drug-induced mitochondrial dysfunction

In Vitro and In Vivo Assessment of Drug-Induced Mitochondrial Dysfunction... 

Dykens, J.a.W.Y. (2008) Drug-Induced Mitochondrial dysfunction, John Wiley and Sons. 

Hynes J, Nadanaciva S, Swiss R, Carey C, Kirwan S, WiU Y (2013) A high-throughput dual parameter assay for assessing drug-induced mitochondrial dysfunction provides additional predic-tivity over two established mitochondrial toxicity assays. Toxicol In Vitro 27, 560-9. 

Mehta R, Chan K, Lee O, Tafazoli S, O Brien P (2008) Drug-associated mitochondrial toxicity. In Drug-Induced Mitochondrial Dysfunction, Eds Dykens JA, Will Y. John Wiley Sons, Inc., Hoboken, NJ, 71-126. 

Nadanaciva S, Rana P, Beeson GC, Chen D, Fenick DA, Beeson CC, Will Y (2012) Assessment of drug-induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96-weU platform. J Bioenerg Biomembr 44, 421-37. 

R. W. Wiseman and J. A. L. Jeneson, Noninvasive Assessment of Mitochondrial Function Using Nuclear Magnetic Resonance Spectroscopy , in Drug-Induced Mitochondrial Dysfunction, eds. J. A. Dykens and Y. Will, John Wiley Sons, Inc., Hoboken, N.J., 2008, p. 555. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

Such imbalanced antioxidant systems in schizophrenia could lead to oxidative stress- and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane polyunsaturated fatty acids (PUFAs). Decrease in membrane phospholipids in blood cells of psychotic patients (Keshavan et al., 1993 Reddy et al., 2004) and fibroblasts from drug-naive patients (Mahadik et al., 1994) as well as in postmortem brains (Horrobin et al., 1991) have indeed been reported. It has also been suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients (Pettegrewet al., 1991 Yao et al., 2002). Recently, a microarray and proteomic study on postmortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia (Prabakaran et al., 2004). Mitochondrial dysfunction in schizophrenia has also been observed by Ben-Shachar (2002) and Altar et al. (2005). As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Thus, a deficit in glutathione (GSH) or immobilization stress induce greater increase in lipid peroxidation and protein oxidation in mitochondrial rather than in cytosolic fractions of cerebral cortex (Liu et al., 1996). 

Labbe G, Pessayre D, Fromenty B (2008) Drug-induced liver injury through mitochondrial dysfunction mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 22(4) 335-353... 

Kashimshetty, R., Desai, V.G., Kale, V.M., Lee, T., Moland, C.L., Branham, W.S., New, L.S.,Chan, E.C.,Younis, H., Boelsterh, U.A. (2009). Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicology and Applied Pharmacology, 238, 150-159. 

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