Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model

Parvaneh Espandiari; Howard P. Glauert; Hans Joachim Lehmler; Eun Y. Lee; Cidambi Srinivasan; Larry W. Robertson

doi:10.1093/toxsci/kfh097

Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model

Parvaneh Espandiari, Howard P. Glauert, Hans Joachim Lehmler, Eun Y. Lee, Cidambi Srinivasan, Larry W. Robertson

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39 Scopus citations

Abstract

We recently reported that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 μmol/kg), dihydroxy (200 μmol/kg), and quinone (100 μmol/ kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of γ-glutamyl transpeptidase-positive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.

Original language	English
Pages (from-to)	41-46
Number of pages	6
Journal	Toxicological Sciences
Volume	79
Issue number	1
DOIs	https://doi.org/10.1093/toxsci/kfh097
State	Published - May 2004

Bibliographical note

Funding Information:
We thank Ms. Cynthia Long, Divinia Stemm, Izabela Korwel, and Drs. Gabriele Ludewig, Nilufer Tampal, and Job Tharappel for their assistance during this research. This study was supported by grant number P42 ES 07380 from the National Institute of Environmental Health Sciences and by the Kentucky Agricultural Experiment Station. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Environmental Health Sciences, National Institutes of Health.

Keywords

Altered hepatic foci
Hepatocarcinogenesis
Initiation
PCB 3
Polychlorinated biphenyls (PCBs)
Solt-Farber

ASJC Scopus subject areas

Toxicology

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10.1093/toxsci/kfh097

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title = "Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model",

abstract = "We recently reported that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 μmol/kg), dihydroxy (200 μmol/kg), and quinone (100 μmol/ kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of γ-glutamyl transpeptidase-positive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.",

keywords = "Altered hepatic foci, Hepatocarcinogenesis, Initiation, PCB 3, Polychlorinated biphenyls (PCBs), Solt-Farber",

author = "Parvaneh Espandiari and Glauert, {Howard P.} and Lehmler, {Hans Joachim} and Lee, {Eun Y.} and Cidambi Srinivasan and Robertson, {Larry W.}",

note = "Funding Information: We thank Ms. Cynthia Long, Divinia Stemm, Izabela Korwel, and Drs. Gabriele Ludewig, Nilufer Tampal, and Job Tharappel for their assistance during this research. This study was supported by grant number P42 ES 07380 from the National Institute of Environmental Health Sciences and by the Kentucky Agricultural Experiment Station. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Environmental Health Sciences, National Institutes of Health.",

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AU - Espandiari, Parvaneh

AU - Glauert, Howard P.

AU - Lehmler, Hans Joachim

AU - Lee, Eun Y.

AU - Srinivasan, Cidambi

AU - Robertson, Larry W.

N1 - Funding Information: We thank Ms. Cynthia Long, Divinia Stemm, Izabela Korwel, and Drs. Gabriele Ludewig, Nilufer Tampal, and Job Tharappel for their assistance during this research. This study was supported by grant number P42 ES 07380 from the National Institute of Environmental Health Sciences and by the Kentucky Agricultural Experiment Station. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Environmental Health Sciences, National Institutes of Health.

PY - 2004/5

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N2 - We recently reported that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 μmol/kg), dihydroxy (200 μmol/kg), and quinone (100 μmol/ kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of γ-glutamyl transpeptidase-positive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.

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KW - Solt-Farber

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Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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