Drug-associated mitochondrial toxicity and its detection.
Mitochondrial dysfunction is a fundamental mechanism in the pathogenesis of several significant toxicities in mammals, especially those associated with the liver, skeletal and cardiac muscle, and the central nervous system. These changes can also occur as part of the natural aging process and have been linked to cellular mechanisms in several human disease states including Parkinson's and Alzheimer's, as well as ischemic perfusion injury and the effects of hyperglycemia in diabetes mellitus. Our knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide the pharmaceutical scientist in anticipating mitochondrial toxicity. Recognition that maintenance of the mitochondrial membrane potential is essential for normal mitochondrial function has resulted in the development of predictive cell-based or isolated mitochondrial assay systems for detecting these effects with new chemical entities. The homeostatic role of some uncoupling proteins, differences in mitochondrial sensitivity to toxicity, and the pivotal role of mitochondrial permeability transition (MPT) as the determinant of apoptotic cell death are factors that underlie the adverse effects of some drugs in mammalian systems. In order to preserve mitochondrial integrity in potential target organs during therapeutic regimens, a basic understanding of mitochondrial function and its monitoring in the drug development program are essential. Toward this end, this review focuses on two topics, (1) the specific effects of xenobiotics on mitochondrial structure and function and (2) a summarization of current methods for quantifying these changes in a preclinical toxicology laboratory.
Amacher
David E
DE
Worldwide Safety Sciences, MS 8274-1227, Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA. david.e.amacher@pfizer.com
D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000502:physiology