Reduction of Tumorigenicity and of Dihydrodiol Formation by Fluorine Substitution in the Angular Rings of Dibenzo(a, i)pyrene

The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo(a, i)pyrene, 2-fluorodibenzo(a, i)pyrene, 3-fluorodibenzo(a, i)pyrene, and 2,10-difluorodibenzo(a, i)py-rene were compared. After an initiating dose of 500 μg, followed by promotion with tetradecanoylphorbol acetate, di-benzo(a, i)pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluoro-dibenzo(a, i)pyrene (85%; 1.7 tumors/mouse); 3-fluorodi-benzo(a, i)pyrene (80%; 3.1 tumors/mouse); and 2,10-difluo-rodibenzo(a, i)pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 μg, only dibenzo(a, i)pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydi-benzo(a,/)pyrene was identified as a metabolite of dibenzo(a, i)pyrene formed by the 9000 x g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydiben-zo(a, i)pyrene. The formation of these angular ring dihydrodiols was inhibited in the metabolism of 2-fluorodiben-zo(a, Opyrene and 3-fluorodibenzo(a, i)pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-di-fluorodibenzo(a, i)pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydi-benzo(a, i)pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo(a, i)pyrene.