The food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline: A conformational analysis of its major DNA adduct and comparison with the 2-amino-3-methylimidazo[4,5-f]quinoline adduct

The heterocyclic amine 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of a group of heterocyclic amine carcinogens that exists in cooked meat and fish. It causes mutations in bacterial and mammalian assays and induces tumors in mammals. MeIQx is converted within cells to a reactive derivative which forms a major covalent adduct at carbon-8 of guanine in DNA. This adduct may alter the DNA conformation at critical stages of the replicative process, and cause mutations which initiate the carcinogenic process. Atomic resolution structures of the MeIQx-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics/energy minimization search to locate feasible structures for the major MeIQx adduct in DNA, using the sequence d(5′-C1-G2-C3-G4[IQ]-C5-G6-C7-3′)· d(5′-G8-C9-G10-C11-G12-C13-G14-3′) with MeIQx modification at G4. We have created 1152 starting conformations which uniformly sampled each of the three flexible torsion angles that govern the MeIQx-DNA orientation at 15° intervals, and minimized their energy. A mixture of conformations was generated, which were separated into families according to the position of the ring system of the carcinogenic amine: major groove, minor groove, and base-displaced-intercalated. While a generally similar mixture had been generated previously for the related carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) [Wu, X., et al. (1999) Chem. Res. Toxicol. 12, 895-905], differences were found which could be rationalized in terms of the additional methyl group in the MeIQx.