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 i nduces tumors in mammals. MeIQx is converted within cells to a reactive der ivative 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 replic ative process, and cause mutations which initiate the carcinogenic process. Atomic resolution structures of the MeIQx-damaged DNA are not yet availabl e experimentally. We have carried out an extensive molecular mechanics/ener gy minimization search to locate feasible structures for the major MeIQx ad duct 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 1 152 starting conformations which uniformly sampled each of the three flexib le torsion angles that govern the MeIQx-DNA orientation at 15 degrees inter vals, and minimized their energy. A mixture of conformations was generated, which were separated into families according to the position of the ring s ystem of the carcinogenic amine: major groove, minor groove, and base-displ aced-intercalated. While a generally similar mixture had been generated pre viously 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 w ere found which could be rationalized in terms of the additional methyl gro up in the MeIQx.