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 language | English (US) |
|---|---|
| Pages (from-to) | 18-24 |
| Number of pages | 7 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 159 |
| Issue number | 1 |
| DOIs | |
| State | Published - Aug 15 1999 |
| Externally published | Yes |
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Keywords
- Accelerator mass spectrometry (AMS)
- Disinfectant
- DNA adduct
- Fungicide
- Ortho-phenylphenol (OPP)
- Pesticide
- Protein adduct
- Rat
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Dose-dependent binding of ortho-phenylphenol to protein but not DNA in the urinary bladder of male F344 rats. / Kwok, E. S C; Buchholz, B. A.; Vogel, J. S.; Turteltaub, Ken W; Eastmond, D. A.
In: Toxicology and Applied Pharmacology, Vol. 159, No. 1, 15.08.1999, p. 18-24.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dose-dependent binding of ortho-phenylphenol to protein but not DNA in the urinary bladder of male F344 rats
AU - Kwok, E. S C
AU - Buchholz, B. A.
AU - Vogel, J. S.
AU - Turteltaub, Ken W
AU - Eastmond, D. A.
PY - 1999/8/15
Y1 - 1999/8/15
N2 - 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.
AB - 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.
KW - Accelerator mass spectrometry (AMS)
KW - Disinfectant
KW - DNA adduct
KW - Fungicide
KW - Ortho-phenylphenol (OPP)
KW - Pesticide
KW - Protein adduct
KW - Rat
UR - http://www.scopus.com/inward/record.url?scp=0033567104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033567104&partnerID=8YFLogxK
U2 - 10.1006/taap.1999.8722
DO - 10.1006/taap.1999.8722
M3 - Article
C2 - 10448121
AN - SCOPUS:0033567104
VL - 159
SP - 18
EP - 24
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -