Mutagenicity and cytotoxicity of benz[ a ]anthracene diol epoxides and tetrahydro-epoxides: Exceptional activity of the bay region 1,2-epoxides

Three diastereomeric pairs of diol epoxides, two tetrahydro-epoxides, and the K-region oxide of the polycyclic aromatic hydrocarbon benz[a ]anthracene were evaluated for mutagenic activity in strain TA 100 ofSalmonella typhimurium and in line V79-6 of Chinese hamster lung cells. The two diastereomeric 1,2-epoxides of thetrans -3,4-dihydrodiol of benz[a ]anthracene are 15 to 35 times more mutagenic to the bacteria and 65 to 125 times more mutagenic to the mammalian cells than are the diastereomeric pairs of benz[a ]anthracene-8,9-diol-10,11-epoxides or benz[a ]anthracene-10,11-diol-8,9-epoxides. 1,2-Epoxy-1,2,3,4-tetrahydrobenz[a ]anthracene is the most mutagenic and cytotoxic of the nine derivatives and is 5 and 25 times more mutagenic than 3,4-epoxy-1,2,3,4-tetrahydrobenz[a ]anthracene in bacterial and mammalian cells, respectively. In either test system, benz[a ]anthracene 5,6-oxide (K-region oxide) has less than 10% of the activity of any of the 1,2-epoxides derived from benz[a ]anthracene. The relative stabilities of the derivatives in aqueous solution do not account for the differences in mutagenic activity because the more mutagenic derivatives tend to be less stable. The benz[a ]anthracene diol epoxides, like the benzo[a ]pyrene diol epoxides, are refractory to the action of epoxide hydrase. The exceptional mutagenic activity of the 1,2-epoxide derivatives of benz[a ]anthracene is consistent with and supportive of the hypothesis that bay region epoxides on saturated, angular benzo-rings of unsubstituted polycyclic aromatic hydrocarbons are ultimate carcinogens.