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

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

Journal article

Open access

Peer reviewed

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

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

Toxicological sciences, Vol.79(1), pp.41-46

05/2004

DOI: 10.1093/toxsci/kfh097

PMID: 14976334

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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 micromol/kg), dihydroxy (200 micromol/kg), and quinone (100 micromol/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 gamma-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.

Liver - pathology

Carcinogens - adverse effects

Rats, Inbred F344

Liver Neoplasms, Experimental - chemically induced

Biphenyl Compounds - adverse effects

Body Weight - drug effects

Male

Carcinogens - metabolism

Liver Neoplasms, Experimental - prevention & control

2-Acetylaminofluorene - administration & dosage

Biphenyl Compounds - metabolism

gamma-Glutamyltransferase - chemistry

Liver - drug effects

Quinones - adverse effects

Time Factors

Diethylnitrosamine - administration & dosage

Diethylnitrosamine - adverse effects

Carcinogens - chemistry

Biphenyl Compounds - chemistry

Quinones - metabolism

Drug Evaluation, Preclinical - methods

Quinones - chemistry

Drug Administration Schedule

Hydroxylation

Administration, Oral

Carbon Tetrachloride - administration & dosage

Injections, Intraperitoneal

Rats

gamma-Glutamyltransferase - biosynthesis

Liver - chemistry

Organ Size - drug effects

Adenoma, Liver Cell - chemically induced

Animals

Models, Biological

Intubation, Intratracheal

Details

Title: Subtitle: Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model
Creators: Parvaneh Espandiari - Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA
Howard P Glauert
Hans-Joachim Lehmler
Eun Y Lee
Cidambi Srinivasan
Larry W Robertson
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.79(1), pp.41-46
Publisher: United States
DOI: 10.1093/toxsci/kfh097
PMID: 14976334
ISSN: 1096-6080
eISSN: 1096-0929
Grant note: P42 ES013661 / NIEHS NIH HHS
Language: English
Date published: 05/2004
Academic Unit: Occupational and Environmental Health
Record Identifier: 9984001093502771

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