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Publication Detail

Title: An intercalation inhibitor altering the target selectivity of DNA damaging agents: synthesis of site-specific aflatoxin B1 adducts in a p53 mutational hotspot.

Authors: Kobertz, W R; Wang, D; Wogan, G N; Essigmann, J M

Published In Proc Natl Acad Sci U S A, (1997 Sep 02)

Abstract: Aflatoxin B1 (AFB1) is a potent human carcinogen implicated in the etiology of hepatocellular carcinoma. Upon metabolic activation to the reactive epoxide, AFB1 forms DNA adducts primarily at the N7 position of guanines. To elucidate more fully the molecular mechanism of AFB1-induced mutagenesis, an intercalation inhibitor was designed to probe the effects of intercalation by AFB1 epoxide on its reaction with DNA. DNA duplexes were prepared consisting of a target strand containing multiple potentially reactive guanines and a nontarget strand containing a cis-syn thymidine-benzofuran photoproduct. Because the covalently linked benzofuran moiety physically occupies an intercalation site, we reasoned that such a site would be rendered inaccessible to AFB1 epoxide. By strategic positioning of this intercalation inhibitor in the intercalation site 5' to a specific guanine, the adduct yield at that site was greatly diminished, indicating that intercalation by AFB1 epoxide contributes favorably to adduct formation. Using this approach it has been possible to simplify the production of site-specifically modified oligonucleotides containing AFB1 adducts in the sequence context of a p53 mutational hotspot. Moreover, we report herein isolation of site-specifically AFB1-modified oligonucleotides in sequences containing multiple guanines. Use of intercalation inhibitors will facilitate both investigation of the ability of other carcinogens to intercalate into DNA and the synthesis of specific carcinogen-DNA adducts.

PubMed ID: 9275165 Exiting the NIEHS site

MeSH Terms: Aflatoxin B1*/chemical synthesis; Aflatoxin B1*/genetics; Aflatoxin B1*/toxicity; Binding Sites/genetics; Carcinogens/chemical synthesis; Carcinogens/toxicity*; Carcinoma, Hepatocellular/genetics*; DNA Damage/drug effects*; Humans; Liver Neoplasms/genetics*; Mutagenesis, Site-Directed; Mutation; Tumor Cells, Cultured; Tumor Suppressor Protein p53/genetics*

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