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

Jean Gauvin, Suse Broyde, Robert Shapiro

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)476-482
Number of pages7
JournalChemical Research in Toxicology
Volume14
Issue number5
DOIs
StatePublished - 2001

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2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline
2-amino-3-methylimidazo(4,5-f)quinoline
DNA Adducts
Mutagens
Amines
Food
Carcinogens
DNA
Conformations
Nucleic Acid Conformation
Mutation
Guanine
Mechanics
Meat
Mammals
Fishes
Carbon
Molecular mechanics
Meats
Torsional stress

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

@article{9ca076c2ed32423b8a04daeb6df8c237,
title = "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",
abstract = "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.",
author = "Jean Gauvin and Suse Broyde and Robert Shapiro",
year = "2001",
doi = "10.1021/tx000144r",
language = "English (US)",
volume = "14",
pages = "476--482",
journal = "Chemical Research in Toxicology",
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publisher = "American Chemical Society",
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TY - JOUR

T1 - The food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline

T2 - A conformational analysis of its major DNA adduct and comparison with the 2-amino-3-methylimidazo[4,5-f]quinoline adduct

AU - Gauvin, Jean

AU - Broyde, Suse

AU - Shapiro, Robert

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

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