Quinoid metabolites of 4-monochlorobiphenyl induce gene mutations in cultured Chinese hamster v79 cells.
4-Monochlorobiphenyl (PCB3) is a component of commercial polychlorinated biphenyl (PCB) products and is an airborne environmental pollutant. Our recent study with transgenic Fischer 344 rats revealed the mutagenic potential of PCB3 in the livers of male rats. PCB3 is converted in vitro to hydroxylated metabolites, to hydroquinones (HQs, e.g., 2',5'-HQ and 3',4'-HQ), and can be further oxidized to quinones (Qs, e.g., 2',5'-Q and 3',4'-Q). This raises the question whether the mutagenic potential of PCB3 is due to the mutagenicity of PCB3 itself or of one of the metabolites. In this study, we investigated the mutagenicity of PCB3, of the monohydroxylated metabolites 2'-hydroxy (HO)-, 3'-HO-, and 4'-HO, of the HQs 3',4'-HQ and 2',5'-HQ and of the Qs 3',4'-Q and 2',5'-Q in cultured Chinese hamster V79 cells. The induction of gene mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene locus by selection with 6-thioguanine. The induction of chromosome and genome mutations was assessed using the micronucleus assay and immunochemical differentiation of micronuclei containing whole chromosomes (kinetochore positive) and DNA fragments (kinetochore negative). The induction of chromosome and genome mutations, detected as micronuclei, was only observed at higher, cytotoxic concentrations of monohydroxylated, catecholic, and quinoid metabolites of PCB3. However, both PCB3-Qs induced a significant increase in the mutant frequency of the hprt gene and did so at submicromolar concentrations. Thus, the present study demonstrates for the first time the mutagenicity of PCB3 metabolites in mammalian cells and identifies quinoid metabolites of PCB3 as potential ultimate mutagens.
Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe (TH), Kaiserstrasse 12, D-76131 Karlsruhe, Germany.
Markus Alexander
MA
Zettner
Susanne
S
Flor
Gabriele
G
Ludewig
Jörg
J
Wagner
Larry W
LW
Robertson
Leane
L
Lehmann
D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D006900:Hydroxylation; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009154:Mutation; D011809:Quinones / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
D001713:Biphenyl Compounds; D006873:Hydroquinones; D009153:Mutagens; D011809:Quinones; D007041:Hypoxanthine Phosphoribosyltransferase; C006983:4-chlorobiphenyl