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Dose-dependent Differences in the Mutational Profiles of (-)-(1R,2S,3S,4R)-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and Its Less Carcinogenic Enantiomer¹

Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855 [S-J. C. W., R. L. C., X. X. C., K. A. M., C-Q. W., A. H. C.], and Section on Oxidation Mechanisms, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892 [H. Y., D. M. J.]

Chinese hamster V-79 cells were treated with high cytotoxic or low noncytotoxic concentrations of the highly carcinogenic and mutagenic (-)-(1R,2S,3S,4R)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]-phenanthrene [(-)-B[c]PhDE; fjord-region diol epoxide] or its biologically less active (+)-(1S,2R,3R,4S) enantiomer [(+)-B[c]PhDE]. The benzylic 4-hydroxyl group and the epoxide oxygen are trans in both enantiomers. Independent 8-azaguanine-resistant clones were isolated. The coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene was amplified by reverse transcription-PCR and sequenced. For (-)-B[c]PhDE, mutation frequencies were 10- or 356-fold above background for the low (0.01–0.1 µM; 97% cell survival) or high (1.0–1.25 µM; 26% cell survival) doses, respectively. For the high dose group, 20 of 64 base substitutions occurred at GC base pairs (31%) and 44 at AT base pairs (69%). For the low-dose group, 6 of 55 base substitutions were at GC base pairs (11%), and 49 were at AT base pairs (89%). For the less active (+)-B[c]PhDE, mutation frequencies were 17- or 372-fold above background for the low (0.12–0.5 µM; 95% cell survival) or high (2.0–3.0 µM; 31% cell survival) doses, respectively. In contrast to the results with the (-)-B[c]PhDE, both the high- and the low-dose groups for (+)-B[c]PhDE gave a 50:50 distribution of base substitution at GC versus AT base pairs. Our data indicate that: (a) transversions were the predominant base substitutions observed for both the (+)- and (-)-enantiomers of B[c]PhDE; (b) (-)-B[c]PhDE showed high selectivity for causing ATTA transversions, whereas considerably less selectivity was observed for (+)-B[c]PhDE; (c) (-)-B[c]PhDE had a different hot spot profile for base substitutions than did (+)-B[c]PhDE, but some common hot spots were observed for both compounds; and (d) decreasing the dose of (-)-B[c]PhDE increased the proportion of mutations at AT base pairs and decreased those at GC base pairs, but this was not observed for (+)-B[c]PhDE.

¹ Supported in part by NIH Grants CA49756 and ES05022.

² To whom requests for reprints should be addressed, at Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, P. O. Box 789, Piscataway, NJ 08855.

³ William M. and Myrle W. Garbe Professor of Cancer and Leukemia Research.

Received 2/19/96. Accepted 6/19/96.

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