Mutagenic specificity of a potent carcinogen, benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide, which reacts with adenine and guanine in DNA.

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Mutations were induced in the supF gene of the pS189 shuttle vector by treatment with optically active benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide in vitro and replication in human cells. The induced mutation frequency was 60-fold greater than the spontaneous rate, and most of the mutations analyzed were transversions (86%), which principally consisted of similar numbers of A.T----T.A and G.C----T.A changes. The unusual susceptibility of A.T pairs to mutation by this chemical agent is consistent with its chemical reactivity toward adenine and argues that the mutations are targeted to the adducts formed. The central base in the sequences 5'-AGA-3', 5'-AAC-3', and 5'-GAG-3' was particularly susceptible to mutation. Twelve "hotspots" in the supF gene accounted for most mutations seen. Some of these hotspots differed from those found by others for racemic benzo[a]pyrene dihydrodiol epoxide and, even when a hotspot was common, the mutagenic changes were not always the same. Although adenine insertion opposite a noninstructional lesion could account for most of the data, no single mutagenic mechanism could encompass all of it. The cellular machinery that converts chemical damage to mutations must determine the mutational result to a large extent, but the findings herein show that the chemical agent itself plays a large role in determining both the location and the nature of the mutations that arise.

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