H2AX, MDM2 AND P53 PHOSPHORYLATION ARE DIFFERENTLY AFFECTED BY BAY- AND FJORD-REGION DIOL EPOXIDES DERIVED FROM CARCINOGENIC POLYCYCLIC AROMATIC HYDROCARBONS

Abstract

The human lung cancer cell line A549 was exposed to diol epoxides (DEs) and the effect on DNA damage signaling proteins was studied. The DEs used were derived from the bay-region PAHs chrysene; CDE and dibenz[a,h]anthracene; DBADE, or the fjord-region PAHs benzo[c]chrysene; B[c]CDE, benzo[g]chrysene; B[g]CDE and benzo[c]phenanthrene; B[c]PhDE. All DEs induced a rapid response on Mdm2, p53 and histone H2AX phosphorylation, where Mdm2 was the most sensitive marker of DNA damage. Fjord-region DEs induced a stronger and more persistent effect on the proteins studied than the bay-region DEs. This variance is likely to reflect differences in adduct recognition and handling by nucleotide excision repair. The stimulating effect of DEs on histone H2AX phosphorylation demonstrated that, in addition to DNA strand breaks and UV-induced photoproducts, stable and bulky DNA-adducts also possess this capacity.