Incubation of either o-bromophenol or 2-bromohydroquinone with rat liver microsomes and 0.25 mM 35S-glutathione (GSH) gave rise to several isomeric 35S-GSH conjugates. A mixture of these isomeric GSH conjugates was prepared chemically and two were purified by HPLC; 1H-NMR spectroscopy revealed that one was 2-bromo-3-(glutathion-S-yl)hydroquinone and the other was a disubstituted GSH conjugate which could be either 2-bromo-3,5-(diglutathion-S-yl)hydroquinone or 2-bromo-3,6-(diglutathion-S-yl)hydroquinone. Injection of the disubstituted GSH conjugate intravenously to rats caused substantial elevations in blood urea nitrogen levels. Treatment of rats with AT-125 (Acivicin; NSC 163501; 10 mg/kg ip) caused a substantial inhibition of kidney γ-glutamyl transpeptidase activity and decreased 2-bromohydroquinone-mediated elevations in blood urea nitrogen. These findings are consistent with the view that the kidney necrosis observed after administration of either bromobenzene (1), o-bromophenol (2), or 2-bromohydroquinone (3) might be due to part of 2-bromohydroquinone GSH conjugates formed in the liver and subsequently transported to the kidney and converted to ultimate nephrotoxic metabolite(s).
|Original language||English (US)|
|Number of pages||7|
|Journal||Drug Metabolism and Disposition|
|State||Published - 1985|
ASJC Scopus subject areas
- Pharmaceutical Science