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

Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [A. W. W., R. L. C., M. K., A. H. C., W. L.]; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [D. M. J.]; and Great Lakes Laboratory, State University of New York, College at Buffalo, Buffalo, New York 14222 [H. C. S., S. K.]

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 expoxides 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.

¹ To whom requests for reprints should be addressed.

² Present address: Department of Chemical Biology and Pharmacognosy, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789.

³ Supported in part by Grant IROIES03346 from the National Institute of Environmental Health Sciences, Department of Health and Human Services.

Received 5/22/89. Revised 9/14/89. Accepted 9/21/89.