The mechanisms by which various chemicals cause nephrotoxicity are poorly understood. It has recently been demonstrated that glutathione (GSH) conjugation with xenobiotics can result in the formation of reactive intermediates and the kidney appears particularly susceptible to the toxic effects of these conjugates. GSH dependent metabolic activation within the kidney probably has greater toxicological significance than that mediated by the cytochrome P-450 dependent mono-oxygenases. This is because of the relatively low activity of renal P-450, the high activity of GSH related enzymes and the rapid turnover of GSH within the kidney. However little is known of the metabolic and pathologic mechanisms by which GSH and cysteine conjugates elicit nephrotoxicity nor of those factors which regulate the generation of potentially reactive thiols from GSH/cysteine conjugates. 2- Bromohydroquinone (2-BHQ) gives rise to a mixture of isomeric mono- and disubstituted GSH conjugates, the latter being a potent nephrotoxin. This is the first example of GSH conjugation, to an aromatic substrate leading to toxicity. GSH conjugation to redox cycling quinones may be a common pathway of toxicity of such compounds. We have established in culture three kidney cell lines of different physiological, morphological and biochemical properties which provide an ideal model with which to study the mechanism of GSH-conjugate mediated nephrotoxicity. The cell lines (i) express widely varying gamma-glutamyl transpeptidase activitives which enable an ideal means of investigating the role of this enzyme in GSH conjugate mediated toxicity (ii) are derived from different anatomical portions of the kidney and thereby provide a model for determining the role of renal transport mechanisms in GSH conjugate mediated toxicity and (iii) likely exhibit differences in prostaglandin synthase activity with which to probe the role of this enzyme in 2-BHQ activation. Moreover, the structure of these 2-BHQ-GSH conjugates and their differential nephrotoxicity provide an ideal model with which to investigate the mechanism and regulation of GSH conjugate mediated nephrotoxicity. The relative contribution of tissue alkylation (via thiol activation) and the redox cycling of the quinone moiety to toxicity can be determined with these conjugates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES004662-01
Application #
3252789
Study Section
Toxicology Study Section (TOX)
Project Start
1987-06-01
Project End
1990-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
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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