Distribution and macromolecular binding of benzo[a]pyrene and two polychlorinated biphenyl congeners in female mice.
PCBs are complete rodent carcinogens and their potent tumor promoting activity has been reported, but their tumor-initiating activity remains controversial. Macromolecular binding of PCB metabolites has been demonstrated in vitro, but this issue remains unclear in vivo. The purpose of this study was to determine the binding affinity of 4-chlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl to proteins and DNA in vivo. C57/BL6 female mice were treated intraperitoneally with hepatic enzyme inducers (phenobarbital and beta-naphthoflavone) and then with 14C-labelled polychlorinated biphenyls or benzo[a]pyrene. The short-term distribution of labeled compounds into liver, lungs and kidneys and into different sub-cellular fractions of these tissues was assessed and the DNA and proteins from the 700 x g pellet were further purified to assess covalent binding. All compounds were distributed in low amounts into the liver, kidneys and lungs, with the greatest accumulation in the liver, and the lowest in lungs. In all tissues, test compounds were mostly found in cytosols and organellar pellets (10,000 x g), and lower amounts were present in nuclear pellets (700 x g) and microsomes. In lungs and kidneys, only benzo[a]pyrene showed significant covalent binding to proteins. In the liver, protein binding indices were significant for all compounds (P<0.05), but no significant binding of the test compounds to DNA could be demonstrated with this approach. Our results suggest that at the 24 h time point, all compounds were activated to electrophilic intermediates prone to macromolecular binding. Hepatic proteins apparently act as a sink for PCB-derived electrophiles, thus preventing detectable levels of covalent binding to hepatic DNA or to proteins in less metabolically active tissues.
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Graduate Center for Toxicology, 306 Health Sciences Research Building, University of Kentucky Medical Center, Lexington, KY 40536-0305, USA.
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Espandiari
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Robertson
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D000818:Animals; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D002458:Cell Fractionation; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics*; D011485:Protein Binding; D014018:Tissue Distribution
D001713:Biphenyl Compounds; D002273:Carcinogens; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D001564:Benzo(a)pyrene; D004247:DNA; D011078:Polychlorinated Biphenyls; C006983:4-chlorobiphenyl; C028451:3,4,3',4'-tetrachlorobiphenyl