Genetic toxicity of 2-acetylaminofluorene, 2-aminofluorene and some of their metabolites and model metabolites

Heflich, Robert H.; Neft, Robin E.

doi:10.1016/0165-1110(94)90025-6

Cited by 226 publications

(223 citation statements)

References 684 publications

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“…The C8-AAF adduct was shown to exist predominantly (∼70%) in the base-displaced intercalated conformation in a sequence in which the modified dGuo was flanked by dCyd, as is the case for the G 3 -position of the NarI sequence (42). Cho and Zhou utilized a C7-fluorinated AAF-derivative and 19 F NMR spectroscopy to examine the conformational heterogeneity of the C8-dGuo adduct. These studies showed that the C8-(7-fluoro-AAF) adduct adopted two distinct base-displaced intercalated conformations in a local -GGA-sequence that differed by the torsional angle of the N-acetyl group (43).…”

Section: Thermal Melting (T M ) Studies Of Iq-adducted Oligo-nucleotidesmentioning

confidence: 99%

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Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Elmquist

Wang

Stover

et al. 2007

Chem. Res. Toxicol.

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Abstract2-Amino-3-methylimidazo [4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine found in cooked meats. The major DNA adduct of IQ is at the C8-position of dGuo. We have previously reported the incorporation of the C8-IQ adduct into oligonucleotides, namely, the G 1 -position of codon 12 of the N-ras oncogene sequence (G 1 G 2 T) and the G 3 -position of the NarI recognition sequence (G 1 G 2 CG 3 CC) (Elmquist et al. (2004) J. Am. Chem. Soc. 126, 11189-11201). Ultraviolet spectroscopy and circular dichroism studies indicated that the conformation of the adduct in the two oligonucleotides was different, and they were assigned as groove-bound and base-displaced intercalated, respectively. The conformation of the latter was subsequently confirmed through NMR and restrained molecular dynamics studies (Wang et al. (2006) J. Am. Chem. Soc. 128, 10085-10095). We report here the incorporation of the C8-IQ adduct into the G 1 -and G 2 -positions of the NarI sequence. A complete analysis of the UV, CD, and NMR chemical shift data for the IQ protons are consistent with the IQ adduct adopting a minor groove-bound conformation at the G 1 -and G 2 -positions of the NarI sequence. To further correlate the spectroscopic data with the adduct conformation, the C8-aminofluorene (AF) adduct of dGuo was also incorporated into the NarI sequence; previous NMR studies demonstrated that the AF-modified oligonucleotides were in a sequence-dependent conformational exchange between major groove-bound and base-displaced intercalated conformations. The spectroscopic data for the IQ-and AF-modified oligonucleotides are compared. The sequence-dependent conformational preferences are likely to play a key role in the repair and mutagenicity of C8-arylamine adducts.

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Section: Thermal Melting (T M ) Studies Of Iq-adducted Oligo-nucleotidesmentioning

confidence: 99%

“…Perhaps the most well studied of the aromatic amines are 2-aminofluorene (AF) and N-acetyl-2-aminofluorene (AAF) (19). Although structurally similar, these compounds elicit significantly different biological responses.…”

Section: Introductionmentioning

confidence: 99%

Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Elmquist

Wang

Stover

et al. 2007

Chem. Res. Toxicol.

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“…These bulky DNA lesions, if not repaired, can produce mutations during replication that initiate the process of carcinogenesis. In bacteria AF-adducts mostly induce G→T transversions, whereas AAF-adducts cause mostly deletion mutations (3). In mammalian cells, however, both adducts promote sequence dependent base substitution mutations (8).…”

Section: Introductionmentioning

confidence: 99%

“…Arylamines and their nitro derivatives are a major group of mutagens and carcinogens (3,4). The environmental carcinogen 2-nitrofluorene and its amino derivatives are the prototype arylamine carcinogens (5,6).…”

Section: Introductionmentioning

confidence: 99%

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Meneni¹,

Liang²,

Cho³

2007

Journal of Molecular Biology

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SUMMARYAdduct-induced conformational heterogeneity complicates the understanding of how DNA adducts exert mutation. A case in point is the N-deacetylated AF lesion [N-(2′-deoxyguanosin-8-yl)-2-aminofluorene], the major adduct derived from the strong liver carcinogen N-acetyl-2-aminofluorene. Three conformational families have been previously characterized and are dependent on the positioning of the aminofluorene rings: B is in the 'B-DNA' major groove, S is 'stacked' into the helix with base-displacement, and W is 'wedged' into the minor groove. In the present study, we conducted 19 F NMR, CD, Tm, and modeling experiments at various primer positions with respect to a template modified by a fluorine tagged AF-adduct (FAF). In the first set, the FAF-G was paired with C and in the second set it was paired with A. The FAF-G:C oligonucleotides were found to preferentially adopt the B-or S-conformers while the FAF-G:A mismatch ones preferred the B-and W-conformers. The conformational preferences of both series were dependent on temperature and complementary strand length; the largest differences in conformation were displayed at lower temperatures. The CD and Tm results are in general agreement with the NMR data. Molecular modeling indicated that the aminofluorene moiety in the minor groove of the W-conformer would impose a steric clash with the tight-packing amino acid residues on the DNA binding area of the Bacillus fragment (BF), a replicative DNA polymerase. In the case of the B-type conformer, the carcinogenic moiety resides in the solvent-exposed major groove throughout the replication/ translocation process. The present dynamic NMR results, combined with previous primer extension kinetic data by Miller and Grollman, support a model in which adduct-induced conformational heterogeneities at positions remote from the replication fork affect polymerase function through a long-range DNA-protein interaction.

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“…Although the mechanisms of mutagenesis have been studied extensively, the conformational aspects underlying replication and repair efficiencies are not well-understood (3)(4)(5). A case in point is the strong hepatocarcinogen N-acetyl-2-aminofluorene, which reacts with DNA to produce two major C8-substituted dG adducts in vivo: an aminofluorene (AF) 1 Figure 1A) and an acetylaminofluorene (AAF) adduct [N-(2′-deoxyguanosin-8-yl)-2-acetylaminofluorene] (6). The N-deacetylated AF adduct in particular has drawn special attention because of its ability to adopt uniquely different conformations depending on the location of the aminofluorene moiety (1,(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Fluorescence Probing of Aminofluorene-Induced Conformational Heterogeneity in DNA Duplexes

Jain

Reshetnyak²,

Gao³

et al. 2008

Chem. Res. Toxicol.

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Fluorescence spectroscopy was used to study carcinogen-induced conformational heterogeneity in DNA duplexes. The fluorophore 2-aminopurine (AP) was incorporated adjacent (5′) to the lesion (G*) in eight different DNA duplexes [d(5′-CTTCTPG*NCCTC-3′):d(5′-GAGGNXTAGAAG-3′), G* = FAF adduct, P = AP, N = G, A, C, T, and X = C, A] modified by FAF [N-(2′-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene], a fluorine-tagged model DNA adduct derived from the potent carcinogen 2-aminofluorene. Steady-state measurements showed that fluorescence intensity and Stern-Volmer constants (K sv ) derived from acrylamide quenching experiments decreased for all carcinogen-modified duplexes relative to the controls, which suggests greater AP stacking in the duplex upon adduct formation. Conformation-specific stacking of AP with the neighboring adduct was evidenced by a sequence-dependent variation in fluorescence intensity, position of emission maximum, degree of emission quenching by acrylamide, and temperature-dependent spectral changes. The magnitude of stacking was in the order of FAF residue in base-displaced stacked (S) > minor groove wedged (W) > major groove B type (B). This work represents a novel utility of AP in probing adduct-induced conformational heterogeneities in DNA duplexes.

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Genetic toxicity of 2-acetylaminofluorene, 2-aminofluorene and some of their metabolites and model metabolites

Cited by 226 publications

References 684 publications

Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Fluorescence Probing of Aminofluorene-Induced Conformational Heterogeneity in DNA Duplexes

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