2-Bromohydroquinone-induced toxicity to rabbit renal proximal tubules: The role of biotransformation, glutathione, and covalent binding

Rick G. Schnellmann, Terrence J. Monks, Lazaro J. Mandel, Serrine S. Lau

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

2-Bromohydroquinone (BHQ) is a model toxic hydroquinone and plays an important role in bromobenzene-induced nephrotoxicity. Proximal tubules isolated to contain decreased glutathione (GSH) levels were at least twice as sensitive to the GSH depleting effects of BHQ and BHQ-induced mitochondrial dysfunction as were tubules with "normal" (i.e., in vivo) GSH content. The decrease in tubular GSH content resulted from BHQ-GSH conjugate formation. A mono-GSH conjugate (2-bromo-3-(glutathion-S-yl)hydroquinone) and a di-GSH conjugate (2-bromo-3,5- or 6-(diglutathion-S-yl)hydroquinone) were identified. In addition, a glucuronide conjugate was identified (2-bromo-1- or 4-O-glucuronylhydroquinone). BHQ-GSH conjugates were not responsible sponsible for BHQ-induced toxicity since (1) tubules with normal levels of GSH were more resistant to BHQ-induced toxicity even though they formed more BHQ-GSH conjugates than tubules with decreased GSH levels and (2) inhibition of γ-glutamyltranspeptidase did not prevent BHQ-induced toxicity. BHQ-equivalents bound covalently to tubular protein in a concentration-, time-, and temperature-dependent manner with the majority of the binding (61%) occurring during the first 15 min after exposure to 0.2 mm BHQ. Tubules pretreated with GSH underwent less BHQ-protein alkylation and mitochondrial dysfunction, and the amount of BHQ recovered and BHQ-di-GSH conjugate formed increased. These data suggest that BHQ is biotransformed to a reactive intermediate (2-bromoquinone and/or 2-bromosemiquinone) and that this intermediate can react with GSH to form BHQ-GSH conjugates and/or bind covalently to tubular protein which may result in mitochondrial dysfunction and tubular death.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalToxicology and Applied Pharmacology
Volume99
Issue number1
DOIs
StatePublished - Jun 1 1989

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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