ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 41-46 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.
Initiating Activity of 4-Chlorobiphenyl Metabolites in the Resistant Hepatocyte Model
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* Graduate Center for Toxicology, Graduate Center for Nutritional Sciences, Department of Pathology and Laboratory Medicine, and Department of Statistics, University of Kentucky Medical Center, Lexington, Kentucky 40536
Received December 14, 2003; accepted January 26, 2004
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 
-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.
Key Words: polychlorinated biphenyls (PCBs); PCB 3; hepatocarcinogenesis; initiation; Solt-Farber; altered hepatic foci.
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