Urban dust particulate matter alters PAH-induced carcinogenesis by inhibition of CYP1A1 and CYP1B1.
The polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and dibenzo[a,l]pyrene (DB[a,l]P) are well-studied environmental carcinogens, however, their potency within a complex mixture is uncertain. We investigated the influence of urban dust particulate matter (UDPM) on the bioactivation and tumor initiation of B[a]P and DB[a,l]P in an initiation-promotion tumorigenesis model. SENCAR mice were treated topically with UDPM or in combination with B[a]P or DB[a,l]P, followed by weekly application of the promoter 12-O-tetradecanoylphorbol-13 acetate. UDPM exhibited weak tumor-initiating activity but significantly delayed the onset of B[a]P-induced tumor initiation by two-fold. When cotreated with UDPM, DB[a,l]P-treated animals displayed no significant difference in tumor-initiating activity, compared with DB[a,l]P alone. Tumor initiation correlated with PAH-DNA adducts, as detected by (33)P-postlabeling and reversed-phase high-performance liquid chromatography. Induction of cytochrome P450 (CYP)1A1 and 1B1 proteins was also detected following UDPM treatment or cotreatment with B[a]P or DB[a,l]P, indicating PAH bioactivation. Further genotoxicity analyses by the comet assay revealed that cotreatment of UDPM plus B[a]P or DB[a,l]P resulted in increased DNA strand breaks, compared with PAH treatment alone. The metabolizing activities of CYP1A1 and CYP1B1, as measured by the 7-ethoxyresorufin O-deethylation (EROD) assay, revealed that UDPM noncompetitively inhibited CYP1A1 and CYP1B1 EROD activity in a dose-dependent manner. Overall, these data suggest that components within complex mixtures can alter PAH-induced carcinogenesis by inhibiting CYP bioactivation and influence other genotoxic effects, such as oxidative DNA damage. These data further suggest that in addition to the levels of potent PAH, the effects of other mixture components must be considered when predicting human cancer risk.
Courter
Lauren A
LA
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331-7302, USA.
Musafia-Jeknic
Tamara
T
Fischer
Kay
K
Bildfell
Robert
R
Giovanini
Jack
J
Pereira
Cliff
C
Baird
William M
WM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D045424:Complex Mixtures / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004391:Dust; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D018632:Mice, Inbred SENCAR; D010078:Oxazines / Q000378:metabolism; D052638:Particulate Matter / Q000494:pharmacology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000633:toxicity*; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D013997:Time Factors; D014481:United States; D014504:Urban Health
D001580:Benzopyrenes; D002273:Carcinogens; D045424:Complex Mixtures; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004391:Dust; D004791:Enzyme Inhibitors; D010078:Oxazines; D052638:Particulate Matter; D011084:Polycyclic Aromatic Hydrocarbons; D001564:Benzo(a)pyrene; C007649:ethoxyresorufin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C041517:dibenzo(a,l)pyrene