Mutagenicity of Dihydrodiols and Diol Epoxides of Dibenz[0,A|acridine in Bacterial and Mammalian Cells

Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz|a,/t|acridine can form two diastereomeric pairs of these diol epoxides which are not positional!) equivalent as a result of the nitrogen atom at position 7. We have assessed the structure-activity relationships resulting from heterocyclic nitrogen substitution by examining the mutagcnic activity of these four bay-region diol epoxides of dibenz|a,A|acridine in both bacterial and mammalian cells. In strains TA98 and TA 100 of Salmonella typhimurwm, the diastereomeric 10,ll-diol-8,9-epoxides were 20 to 40 times more mutagenie than the corresponding 3,4-diol-l,2-epoxides. Furthermore, in strain TA 100, diben/|a,A]acridine 10,11-dihydrodiol, the expected meta bolic precursor of the 10,11 -diol-8,9-epoxide, was metabolically activated by rat hepatic microsomes up to a 12-fold greater extent than the 3,4dihydrodiol. In Chinese hamster V79 cells, the 10,ll-diol-8,9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3,4-diol1,2-cpoxide counterparts. Quantum mechanical calculations of the pre dicted ease of benzylic carbocation formation at C-l and C-8 from the diol epoxides indicate that the 3,4-diol-1.2-epoxides should be less reac tive due to resonance destabilization of the C-l carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3,4diol-l,2-epoxides may explain their decreased mutagenic activity.