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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh097
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 14, 2003; accepted January 26, 2004
© 2004 Society of Toxicology

Carcinogenicity

Initiating Activity of 4-Chlorobiphenyl Metabolites in the Resistant Hepatocyte Model

Parvaneh Espandiari 1, Howard P. Glauert 2, Hans-Joachim Lehmler 1, Eun Y. Lee 3, Cidambi Srinivasan 4, and Larry W. Robertson 2*

1 Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536 USA
2 Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536 USA; Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, KY 40536 USA
3 Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536 USA; Department of Pathology and Laboratory Medicine, University of Kentucky Medical Center, Lexington, KY 40536 USA
4 Department of Statistics, University of Kentucky Medical Center, Lexington, KY 40536 USA

* To whom correspondence should be addressed. E-mail: larry-robertson{at}uiowa.edu.


  Abstract

We have recently reported that several mono- to tetra-chlorinated 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. Mono-hydroxy (400 µmol/kg), di-hydroxy (200 µmol/kg) and quinone (100 µmol/kg) metabolites of 4-chlorobiphenyl were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 hrs after refeeding they were injected i.p. with metabolites, vehicle, or diethylnitrosamine (DEN; 20 or 40 mg/kg). All animals were treated with selection agents: 3 daily p.o. doses of 2-acetylaminofluorene (2-AAF; 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2ml/kg) followed by 3 additional daily treatments of 2-AAF. Rats were killed two 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 mono-hydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of 4-chlorobiphenyl therefore proceeds via para hydroxylation 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 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.

Key Words: Polychlorinated Biphenyls (PCBs), PCB 3, Hepatocarcinogenesis, Initiation, Solt-Farber, Altered Hepatic Foci .


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