Benzo[ a ]pyrene-7,8-dione is More Mutagenic than Anti -BPDE on p53 and is Dependent on the Generation of Reactive Oxygen Species

Polycyclic aromatic hydrocarbons (PAHs) may cause lung cancer via metabolic activation. p53 is one of the most commonly mutated tumor suppressor genes in this disease. To determine whether PAH o -quinones cause change-in-function mutations in p53 , we employed a yeast reporter system. Treatment of p53 cDNA with ( - )- anti -7,8-dihydroxy-9 f ,10 f -epoxy-7,8,9,10-tetrahydro-benzo[ a ]pyrene, ( anti -BPDE, an ultimate carcinogen) or submicromolar concentrations of BP-7,8-dione under redox-cycling conditions (NADPH and CuCl 2 ) also caused p53 mutagenesis in a dose-dependent manner. It was found that BP-7,8-dione was 80 times more mutagenic than anti -BPDE under these conditions. p53 mutagenesis by BPQ was attenuated by ROS scavengers and completely abrogated by a combination of superoxide dismutase and catalase, indicating that both superoxide anion and hydroxyl radicals were the responsible mutagens. DNA sequencing demonstrated that over 46% of BPQ-induced mutations were G:C to T:A transversions. Together...