Mechanism of Mitochondrial Uncouplers, Inhibitors, and Toxins: Focus on Electron Transfer, Free Radicals, and Structure -Activity Relationships

Authors: Kovacic, Peter; Pozos, Robert S.; Somanathan, Ratnasamy; Shangari, Nandita; O'Brien, Peter J.

Source: Current Medicinal Chemistry, Volume 12, Number 22, October 2005 , pp. 2601-2623(23)

Publisher: Bentham Science Publishers

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Abstract:

The biology of the mitochondrial electron transport chain is summarized. Our approach to the mechanism of uncouplers, inhibitors, and toxins is based on electron transfer (ET) and reactive oxygen species (ROS). Extensive supporting evidence, which is broadly applicable, is cited. ROS can be generated either endogenously or exogenously. Generally, the reactive entities arise via redox cycling by ET functionalities, such as, quinones (or precursors), metal compounds, imines (or iminiums), and aromatic nitro compounds (or reduced metabolites). In most cases, the ET functions are formed metabolically. The toxic substances belong to many categories, e.g., medicinals, industrial chemicals, abused drugs, and pesticides. Structure-activity relationships are presented from the ET-ROS perspective, and also quantitatively. Evidence for the theoretical framework is provided by the protective effect of antioxidants. Among other topics addressed are proton flux, membrane pores, and apoptosis. There is support for the thesis that mitochondrial insult may contribute to illnesses and aging.

Keywords: aging; antioxidants; electron transfer; illness; mitochondria; reactive oxygen species; structure-activity relationship

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/092986705774370646

Affiliations: Department of Chemistry, San Diego State University, San Diego, California 92182-1030, USA.

Publication date: October 1, 2005

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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