September 1, 2015
Journal Article

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 Toxicology and Applied Pharmacology

Abstract

FVB/N mice wild-type, heterozygous or null for the expression of Cyp 1b1 were used in a two-stage skin tumor study to compare the prototypic PAH, benzo[a]pyrene (BaP), to dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, NIST SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited significant reductions in tumor incidence, multiplicity, and progression. In contrast, 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 8 h post-initiation in Cyp 1b1+/+, Cyp 1b1+/- and Cyp 1b1-/- mice. A significant reduction in levels of Cyp 1a1 and Akr 1c14 mRNA was observed in the Cyp 1b1 null (but not het) mice, whereas no impact was observed in mRNA levels of Gst a1, Nqo 1 or Akr 1c18. Cypb1 mRNA levels were not elevated in skin by DBC treatment. The major covalent DNA adducts, dibenozo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in skin . Interestingly, the ratio of cis- to trans-DBCDE-dA adducts was markedly higher in skin than in other target tissues of mouse such as 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. However, loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators.

Revised: November 19, 2015 | Published: September 1, 2015

Citation

Siddens L.K., K.L. Bunde, T.A. Harper Jr., T.J. McQuistan, C.V. Lohr, L.M. Bramer, and K.M. Waters, et al. 2015. 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 Toxicology and Applied Pharmacology. Toxicology and Applied Pharmacology 287, no. 2:149-160. PNWD-SA-10455. doi:10.1016/j.taap.2015.05.019