title: Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression.
abstract: Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant, which may contribute to the development of human cancer. The ultimate carcinogenic BaP metabolite produced by cytochrome P450 enzymes (CYP), such as CYP1A1 and CYP1B1, anti-BaP-7,8-diol-9,10-epoxide, binds covalently to DNA and causes mutations. The levels of various CYP isoforms can be significantly modulated under inflammatory conditions. As the chronic inflammation is known to contribute to carcinogenesis, we investigated interactions of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), and BaP in regulation of the expression of CYP1A1/1B1 and induction of DNA damage in rat liver epithelial WB-F344 cells. TNF-alpha enhanced induction of CYP1B1, while it simultaneously suppressed the BaP-induced CYP1A1 expression. The observed deregulation of CYP1 induction was found to be associated with a significantly enhanced formation of DNA adducts. The elevated DNA damage corresponded with increased phosphorylation of p53 tumor suppressor at Ser-15 residue, enhanced accumulation of cells in the S-phase of cell cycle and potentiation of BaP-induced apoptosis. Inhibition of CYP1B1 by fluoranthene significantly decreased both the formation of DNA adducts and the induction of apoptosis in WB-F344 cells treated with BaP and TNF-alpha, thus suggesting that this isoform might be responsible for genotoxic effects of BaP in nonparenchymal liver cells. Our results seem to indicate that inflammatory conditions might enhance genotoxic effects of carcinogenic polycyclic aromatic hydrocarbons through upregulation of CYP1B1 expression.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, AS CR, 612 65 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Umannová
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.forename: Jan
authors.initials: J
authors.lastname: Topinka
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Nováková
authors.forename: Alena
authors.initials: A
authors.lastname: Milcová
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Jan
authors.initials: J
authors.lastname: Vondrácek
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002460:Cell Line; D065633:Cytochrome P-450 CYP1B1; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D014409:Tumor Necrosis Factor-alpha; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1