Dose-dependent binding of ortho-phenylphenol to protein but not DNA in the urinary bladder of male F344 rats

E. S C Kwok, B. A. Buchholz, J. S. Vogel, Ken W Turteltaub, D. A. Eastmond

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

ortho-Phenylphenol (OPP) is a widely used fungicide and antibacterial agent that is also known to be highly effective in inducing bladder tumors in male F344 rats. At present, neither the role of the urinary bladder in the bioactivation of OPP metabolites nor the nature of the molecular target is understood. To address these issues, we investigated the relationship between OPP dosage and macromolecular adduct formation in the urinary bladder of male F344 rats. Male F344 rats were treated with 0, 15, 50, 125, 250, 500, 1000 mg/kg of OPP and its radiocarbon analogue via oral gavage. The dosed rats were euthanized after 24 h, and the proteins were extracted from the liver, kidney, and bladder. The amount of radioactivity associated with the extracted protein was quantified using highly sensitive accelerator mass spectrometry. Protein binding in liver and kidney exhibited a linear or modest curvilinear relationship over the dose range studied. In the urinary bladder, however, a pronounced nonlinear relationship between protein adduct levels and administered dose was observed. The measured protein adduct levels were in agreement with the predicted concentrations of phenylbenzoquinone based on a proposed mechanism involving free phenylhydroquinone autoxidation in the urine. Unlike protein binding, DNA adducts measured from the same bladder samples did not show a significant difference from the control group. These data are consistent with the hypothesis that OPP is an indirect acting carcinogen, and that regenerative hyperplasia due to OPP-metabolite cytotoxicity and/or binding of OPP metabolites to protein targets may play an important role in OPP-induced bladder carcinogenesis.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalToxicology and Applied Pharmacology
Volume159
Issue number1
DOIs
StatePublished - Aug 15 1999
Externally publishedYes

Keywords

  • Accelerator mass spectrometry (AMS)
  • Disinfectant
  • DNA adduct
  • Fungicide
  • Ortho-phenylphenol (OPP)
  • Pesticide
  • Protein adduct
  • Rat

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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