Mutagenicity of Dihydrodiols and Diol Epoxides of Dibenz[a,h]acridine in Bacterial and Mammalian Cells

Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz[a,h]acridine can form two diastereomeric pairs of these diol epoxides which are not positionally 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 mutagenic activity of these four bay-region diol epoxides of dibenz[a,h]acridine in both bacterial and mammalian cells. In strains TA98 and TA100 of Salmonella typhimurium, the diastereomeric 10, 11-diol-8, 9-epoxides were 20 to 40 times more mutagenic than the corresponding 3,4-diol-1,2-epoxides. Furthermore, in strain TA100, dibenz[a,h]acridine 10,11-dihydrodiol, the expected metabolic 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 3,4-dihydrodiol. In Chinese hamster V79 cells, the 10, 11-diol-8, 9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3, 4-diol-1, 2-epoxide counterparts. Quantum mechanical calculations of the predicted ease of benzylic carbocation formation at C-1 and C-8 from the diol epoxides indicate that the 3, 4-diol-1, 2-epoxides should be less reactive due to resonance destabilization of the C-1 carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3, 4-diol-1,2-epoxides may explain their decreased mutagenic activity.