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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004662-05
Application #
3252793
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1987-06-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Monks, T J; Lau, S S (1998) The pharmacology and toxicology of polyphenolic-glutathione conjugates. Annu Rev Pharmacol Toxicol 38:229-55
Monks, T J; Lau, S S (1997) Biological reactivity of polyphenolic-glutathione conjugates. Chem Res Toxicol 10:1296-313
Monks, T J; Rivera, M I; Mertens, J J et al. (1996) The kidney as a target for biological reactive metabolites: linking metabolism to toxicity. Adv Exp Med Biol 387:203-12
Mertens, J J; Gibson, N W; Lau, S S et al. (1995) Reactive oxygen species and DNA damage in 2-bromo-(glutathion-S-yl) hydroquinone-mediated cytotoxicity. Arch Biochem Biophys 320:51-8
Rivera, M I; Hinojosa, L M; Hill, B A et al. (1994) Metabolism and toxicity of 2-bromo-(diglutathion-S-yl)-hydroquinone and 2-bromo-3-(glutathion-S-yl)hydroquinone in the in situ perfused rat kidney. Drug Metab Dispos 22:503-10
Monks, T J; Lo, H H; Lau, S S (1994) Oxidation and acetylation as determinants of 2-bromocystein-S-ylhydroquinone-mediated nephrotoxicity. Chem Res Toxicol 7:495-502
Rivera, M I; Jones, T W; Lau, S S et al. (1994) Early morphological and biochemical changes during 2-Br-(diglutathion-S-yl)hydroquinone-induced nephrotoxicity. Toxicol Appl Pharmacol 128:239-50
Hill, B A; Kleiner, H E; Ryan, E A et al. (1993) Identification of multi-S-substituted conjugates of hydroquinone by HPLC-coulometric electrode array analysis and mass spectroscopy. Chem Res Toxicol 6:459-69
Monks, T J; Hanzlik, R P; Cohen, G M et al. (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112:2-16
Hill, B A; Monks, T J; Lau, S S (1992) The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity. Toxicol Appl Pharmacol 117:165-71

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