Wallace Kendall B
Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA.
Trends Pharmacol Sci. 2008 Jul;29(7):361-6. doi: 10.1016/j.tips.2008.04.001. Epub 2008 May 22.
The bioenergetic features of mitochondria have long been exploited in the design of pharmacological agents suited to accomplish a desired physiological effect; uncoupling of oxidative phosphorylation to induce weight loss, for example. However, more recent experience demonstrates mitochondria to be unintended off targets of other drug therapies and responsible, at least in part, for the dose-limiting adverse events associated with a large array of pharmaceuticals. Review of the fundamentals of mitochondrial molecular biology and bioenergetics reveals a multiplicity of off targets that can be invoked to explain drug-induced mitochondrial failure. It is this redundancy of mitochondrial off targets that complicates identification of discrete mechanisms of toxicity and confounds QSAR-based design of new small molecules devoid of this potential for mitochondrial toxicity. The present review article briefly reviews the molecular biology and biophysics of mitochondrial bioenergetics, which then serves as a platform for identifying the various potential off targets for drug-induced mitochondrial toxicity.
线粒体的生物能量学特性长期以来一直被用于设计适合实现预期生理效应的药物制剂；例如，氧化磷酸化解偶联以诱导体重减轻。然而，最近的经验表明线粒体是其他药物疗法意想不到的脱靶靶点，并且至少部分地导致了与大量药物相关的剂量限制性不良事件。对线粒体分子生物学和生物能量学基本原理的回顾揭示了多种脱靶靶点，这些靶点可用于解释药物诱导的线粒体功能衰竭。正是线粒体脱靶靶点的这种冗余性使得确定离散的毒性机制变得复杂，并混淆了基于定量构效关系的无线粒体毒性潜力的新小分子设计。本综述文章简要回顾了线粒体生物能量学的分子生物学和生物物理学，然后以此为平台来识别药物诱导的线粒体毒性的各种潜在脱靶靶点。
