title: Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse.
abstract: FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators.
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Bunde
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Tod A
authors.initials: TA
authors.lastname: Harper
authors.affiliation: Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Tammie J
authors.initials: TJ
authors.lastname: McQuistan
authors.affiliation: Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA; College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Applied Statistics and Computational Modeling, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Bramer
authors.affiliation: Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Tilton
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA. Electronic address: david.williams@oregonstate.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA; Superfund Research Center, Oregon State University, Corvallis, OR 97331, USA; Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Baird
mesh_terms: D000818:Animals; D001580:Benzopyrenes; D002273:Carcinogens / Q000633:toxicity*; D003033:Coal Tar / Q000633:toxicity*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000139:chemically induced*; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D003033:Coal Tar; D065633:Cytochrome P-450 CYP1B1
keywords: Cyp1b1; DNA adducts; PAHs; Relative Potency Factor; Skin cancer