Increased toxicity of benzo(a)pyrene-7,8-dihydrodiol in the presence of polychlorobiphenylols.
Benzo(a)pyrene (BaP) and polychlorinated biphenyls (PCBs) often co-exist in contaminated environments. Polychlorobiphenylols (OH-PCBs), formed by CYP-dependent monooxygenation of PCBs, are potent inhibitors of the glucuronidation of hydroxylated BaP metabolites. We hypothesized that OH-PCBs could drive the biotransformation of (-)BaP-7,8-dihydrodiol (BaP-7, 8-D) away from detoxication and towards formation of the reactive metabolite. A mixture of five OH-PCBs with 4-6 Cl atoms was infused into isolated, perfused, biliary intact livers (n=3 fish) removed from 3-methylcholanthrene-induced channel catfish. Controls (n=3) were infused with vehicle. Subsequently, [3H]-BaP-7, 8-D was infused into each liver and bile was collected for 1 h. The livers were taken for analysis of metabolites and DNA adducts. Induction status was confirmed by EROD assay. Bile was analyzed for metabolites. It was found that preinfusion of the mixture of OH-PCBs reduced the extent of glucuronidation of BaP-7, 8-D and increased the formation of DNA adducts 5-fold over controls. GSH conjugates, tetrols and triols were increased in the OH-PCB-infused fish, providing further support for our hypothesis that if the glucuronidation were inhibited, CYP-dependent activation would increase. These studies suggest a mechanism for synergy of toxicity of PAH and PCBs.
James
Margaret O
MO
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, P.O. Box 100485, Gainesville, FL 32610-0485, USA. mojames@ufl.edu
Kleinow
Kevin M
KM
Zhang
Youbo
Y
Zheng
Ran
R
Wang
Liquan
L
Faux
Laura R
LR
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002397:Catfishes / Q000378:metabolism* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008748:Methylcholanthrene; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D014316:Tritium
D004101:Dihydroxydihydrobenzopyrenes; D020719:Glucuronides; D014316:Tritium; C017228:benzo(a)pyrene 7,8-dihydrodiol; D008748:Methylcholanthrene; D004247:DNA; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1