The reactivity of quinones resides in their ability to undergo """"""""redox cycling"""""""" and to create an oxidative stress and/or to react directly with cellular nucleophiles such as protein and non-protein sulfhydryls. Glutathione (GSH) is the major non-protein sulfhydryl present in cells. During prior grant years, the investigators have shown that in contrast to serving a detoxication function, conjugation of quinones with GSH results in the formation of potent and selective nephrotoxicants. Thus, oxidation of 2-bromohydroquinone (2-BrHQ) in the presence of GSH gave rise to several mono- and diGSyl substituted conjugates. Whereas 2-Br-(diGSyl)HQ is a potent and selective nephrotoxicant, the three mono-GSyl isomers exhibited differentially less toxicity. They have also demonstrated that physiological, biochemical and electrochemical factors contribute to the differential toxicity of 2-Br-(GSyl)HQ conjugates. In contrast, the mechanism(s) of 2-Br-(GSyl)HQ-mediated cytotoxicity remain unclear. Since data from original studies support an important role for covalent binding in the nephrotoxicity of 2-Br-(GSyl)HQ conjugates, the present renewal application will focus on the interaction of 2-Br-(GSyl)HQ metabolites with cellular constituents and their role in the initiation and development of cytotoxicity. Attempts to identify the macromolecules to which the reactive metabolites bind will be made in order to determine whether specific targeting occurs in renal tissue and whether such """"""""target"""""""" proteins are ubiquitous or present only in susceptible tissues. In addition, studies into the potential toxicological significance of endogenous quinone-thioethers will be initiated, with particular emphasis on the ability of GSH conjugation, via the subsequent processing of the conjugate through the mercapturic acid pathway, to modulate the ease of quinol oxidation. 1,4-benzothiazine formation from quinone-thioethers, which represent a novel and divergent pathway from the normal route of mercapturic acid synthesis, will be extended to determine the potential toxicological significance of this pathway.
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