Mutagenicity of benzo[a]pyrene-deoxyadenosine adducts in a sequence context derived from the p53 gene

Mutations in the human p53 tumor suppressor gene are prominently linked to sporadic cancers in breast, lung and other tissues. Recent research has sho wn that tobacco-associated cancer in the human lung is related to mutation of the p53 gene mediated by the carcinogen benzo[a]pyrene (BaP), and the mu tations are targeted to DNA "hot spots" at specific codons. In order to gai n insight into the relation between the structures of the adducts formed by BaP at these sites and their mutagenic activities, we have synthesized sit e-specifically modified oligo-nucleotide adducts of the active BaP diol epo xide metabolite (anti-BaPDE). This manuscript reports on the mutagenic cons equences of replication past anti-BaPDE-deoxy-adenosine adducts located wit hin a sequence context related to codon 157 in exon 5 of the p53 gene. In t his sequence context, the adduct derived from the carcinogenic 7R,8S-dihydr odiol 9S,10R-epoxide was much more active as a mutagen than the adduct deri ved from the noncarcinogenic 7S,8R-dihydrodiol 9R,10S-epoxide and the mutat ion found most frequently was an A --> G transition. Since previous studies in other sequence contexts have yielded somewhat different findings, these studies further emphasize the key role played by sequence context in deter mining the mutational properties of carcinogen-DNA adducts. (C) 2000 Elsevi er Science B.V. All rights reserved.