Modulation of Thiols and Other Low-Molecular-Weight Cofactors: Effects on Drug Metabolism and Disease Susceptibility

A brief summary of the pioneering work of Brodie, Gillette, and coworkers on the discovery and development of the concept of chemically reactive intermediates serves as the backdrop for this chapter on approaches to studying how chemicals modify thiols and other cellular nucleophiles. As examples, work is presented on classic hepatotoxicants such as acetaminophen, bromobenzene, carbon tetrachloride, and diquat. Discussion focuses on illustrations of key data and methods to assess lipid peroxidation, oxidant stress, chemically induced depletion of glutathione and protein thiols, and oxidative modification of proteins. Further adaptation of the methodologies and approaches that are discussed to relevant human and live animal models of toxicant action and physiological responses are needed. These strategies and the data that the applications can provide are important, not only for characterization of specific human exposures and toxicities, but also for the evolution of important fundamental principles, concepts, and experimental approaches.