Metabolic activation of PCBs to carcinogens in vivo—A review

Gabriele Ludewig; Leane Lehmann; Harald Esch; Larry W Robertson

doi:10.1016/j.etap.2007.10.029

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Metabolic activation of PCBs to carcinogens in vivo—A review

Journal article

Peer reviewed

Metabolic activation of PCBs to carcinogens in vivo—A review

Gabriele Ludewig, Leane Lehmann, Harald Esch and Larry W Robertson

Environmental toxicology and pharmacology, Vol.25(2), pp.241-246

2008

DOI: 10.1016/j.etap.2007.10.029

PMCID: PMC2364599

PMID: 18452002

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Abstract

Many higher-chlorinated biphenyls, persistent and predominant in foods, are active as promoters in hepatocarcinogenesis. Lower-chlorinated biphenyls, predominating in indoor and outdoor air, are more readily metabolized and therefore shorter lived, ‘episodic’ contaminants. Thus inhalation of such lower-chlorinated biphenyls may expose humans to reactive, possibly genotoxic/carcinogenic intermediates. Lower-chlorinated biphenyls may be metabolized via arene-oxides to mono- and di-hydroxylated intermediates and further to (semi)quinones, highly reactive intermediates. Covalently bound lower-chlorinated biphenyls have been detected in rodent tissues in vivo. We recently showed using the modified Solt–Farber foci assay that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of rats. In a follow-up study of PCB3 (4-chlorobiphenyl) metabolites, only one monohydroxy- and one quinoid-metabolite showed initiating activity, indicating that the metabolic activation of PCB3 proceeds via hydroxylation and oxidation to the 3,4-quinone, the ultimate carcinogen. Since cancer initiation is based on genotoxic event(s), we hypothesized that PCB3 and/or its metabolite(s) are mutagenic in rat liver in vivo. To investigate this, BigBlue ® rats, transgenic for the lacI reporter gene, were exposed to PCB3 and 4-hydroxy-PCB3 (4-HO-PCB3). In male rats the mutant frequency (MF) of lacI in the liver was significantly elevated and the mutation spectrum differed significantly from the control. 4-HO-PCB3 caused a non-significant ( p = 0.115) doubling of the MF compared to the control. These studies prove that lower halogenated biphenyls may be metabolically activated in vivo to genotoxic and initiating intermediates.

4-monochlorobiphenyl

In vivo

Metabolic activation

Transgenic rat

Mutation

Carcinogenesis

PCB

Details

Title: Subtitle: Metabolic activation of PCBs to carcinogens in vivo—A review
Creators: Gabriele Ludewig - Department of Occupational & Environmental Health, College of Public Health, University of Iowa, 100 Oakdale Campus, #234 IREH, Iowa City, IA 52242-5000, USA
Leane Lehmann - Institute of Applied Biosciences, University of Karlsruhe, Kaiserstrasse 12, D-76131 Karlsruhe, Germany
Harald Esch - BASF Aktiengesellschaft, Ludwigshaven, Germany
Larry W Robertson - Department of Occupational & Environmental Health, College of Public Health, University of Iowa, 100 Oakdale Campus, #234 IREH, Iowa City, IA 52242-5000, USA
Resource Type: Journal article
Publication Details: Environmental toxicology and pharmacology, Vol.25(2), pp.241-246
DOI: 10.1016/j.etap.2007.10.029
PMID: 18452002
PMCID: PMC2364599
NLM abbreviation: Environ Toxicol Pharmacol
ISSN: 1382-6689
eISSN: 1872-7077
Publisher: Elsevier BV
Language: English
Date published: 2008
Academic Unit: Occupational and Environmental Health; Iowa Superfund Research Program
Record Identifier: 9983997330502771

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