Long-term effects of a standardized complex mixture of urban dust particulate on the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons in human cells in culture.
Humans are exposed to complex mixtures of polycyclic aromatic hydrocarbons in the atmosphere. We examined the long term effects of a standard reference material (SRM) 1649a over time on the metabolic activation and DNA adduct formation by two carcinogenic PAHs, benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) in the human mammary carcinoma derived cell line MCF-7. PAH-DNA adduct analysis, cytochrome P450 (CYP) enzyme activity, CYP1A1 and CYP1B1 protein expression were determined in cells treated with SRM 1649a alone or SRM 1649a with either BP or DBP for 24 to 120 h. Averaging over time, significantly higher levels of DNA adducts were observed in cells treated with BP or DBP alone than in co-treatments with SRM 1649a and BP or DBP. Ethoxyresorufin O-deethylase assay indicated a significant increase in activity in cells treated with BP alone and co-treated with SRM1649a in comparison to other treatment groups. Induction of CYP1A1 and CYP1B1 protein expression was observed by immunoblots in cells treated with BP alone or in co-treatments of SRM 1649a and BP or DBP. These data demonstrate the influence of the components of SRM 1649a in inhibiting the activation of BP or DBP by CYP enzymes in the formation of DNA adducts. It also suggests that the carcinogenic activity of PAH within a complex mixture may vary with composition and activation of the components present in the complex mixture.
Musafia-Jeknic
Tamara
T
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, 97331, USA.
Mahadevan
Brinda
B
Pereira
Clifford
C
Baird
William M
WM
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics* / Q000633:toxicity; D001580:Benzopyrenes / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D045744:Cell Line, Tumor; D045424:Complex Mixtures / Q000493:pharmacokinetics* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis / Q000187:drug effects; D004338:Drug Combinations; D004391:Dust; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D014504:Urban Health
D001580:Benzopyrenes; D002273:Carcinogens; D045424:Complex Mixtures; D018736:DNA Adducts; D004338:Drug Combinations; D004391:Dust; D001564:Benzo(a)pyrene; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C041517:dibenzo(a,l)pyrene