Differential effects of bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons on Mdm2 and p53 phosphorylation

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4262 The polycyclic aromatic hydrocarbons (PAHs) dibenzo[ a,l ]pyrene (DBP) and benzo[ a ]pyrene (BP) are widespread environmental contaminants and potent carcinogens. The fjord-region DBP is several orders of magnitude more mutagenic/carcinogenic than BP, a fact that can be ascribed to differences in DNA binding specificity/efficiency of their ultimate carcinogenic diol epoxide (DE) intermediates, differences in structural features of the DNA adducts and differences in DNA adduct recognition, repair and subsequent downstream signaling. Moreover, the acute toxicity of DBP far exceeds that of BP and similar PAHs. We have previously characterized the effect of the ultimate carcinogenic diol epoxides, (+)- anti -BPDE and (-)- anti -DBPDE following short exposure times, on Mdm2 and p53 pathways in A549 human lung epithelial carcinoma cells (G. Paajarvi et al., submitted for publication). We found that (+)- anti -BPDE induced stabilization and chromatin binding of Mdm2 phosphorylated at an antibody 2A10-specific epitope. These effects were transient and correlated with transient p53 Ser15 phosphorylation. In contrast DNA adducts of (-)- anti -DBPDE, which are more refractory to removal (Dreij et al., Chem. Res. Toxicol., 18, 655-664, 2005), were associated with lack of Mdm2 stabilization and chromatin binding, and sustained p53 Ser15. Furthermore, adducts of (-)- anti -DBPDE were associated with increased phosphorylation of p53 at Ser46, a phosphorylation site associated with apoptosis. We also concluded that depending on diol epoxide p53 Ser15 phosphorylation and antibody 2A10-site specific phosphorylation of Mdm2 are induced by non-identical signaling pathways. In this study we have exposed A549 cells to several DEs belonging to either the bay or fjord region category in order to see if the differential signaling pathways observed with (+)- anti -BPDE and (-)- anti -DBPDE can be extended to bay and fjord region DEs in general. The results available so far indicate significant response differences. The bay region DEs used here (derived from chrysene and dibenzo[ a,h ]anthracene) seem to induce transient Mdm2 stabilization and p53 Ser15 phosphorylation whereas the fjord region DEs (derived from benzo[ c ]- and benzo[ g ]chrysene, and benzo[ c ]phenanthrene) induce sustained p53 Ser15 phosphorylation and no apparent effect on Mdm2 stabilization. We interpret the results as reflecting differences in adduct regognition/repair efficiency and that this depends on well established differences in structural features of bay and fjord region DEs. As previously observed with (-)- anti -DBPDE, the fjord region DEs induce p53 Ser46 phosphorylation.