Endogenous DNA adducts: Potential and paradox

Marnett, Lawrence J.; Burcham, Philip

doi:10.1021/tx00036a005

Cited by 286 publications

(159 citation statements)

References 185 publications

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“…However, it is not clear whether this adduct is derived from DNA-binding B[a]P metabolites or whether it is an indirect DNA modification that does not contain the B[a]P moiety. It is known that indirect DNA adducts with unknown chemical identity could be generated during metabolism of carcinogens and estrogens [Liehr et al, 1986, Marnett et al, 1993. To distinguish whether Spot 1 is directly derived from B[a]P or is an endogenous DNA adduct formed as a consequence of B[a]P exposure, we compared it with adduct profiles de- Most of these compounds induced DNA adduct formation but none of these adducts is in a location similar to that of Spot 1 under our chromatography conditions (films not shown).…”

Section: Resultsmentioning

confidence: 99%

Characterization of a major aromatic DNA adduct detected in human breast tissues

Wang

Firozi

et al. 2002

Environ and Mol Mutagen

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A bulky DNA adduct (Spot 1) was previously detected in normal adjacent breast tissues of 41% (36/87) of women with breast cancer and in none (0/29) of the noncancer controls by 32 P-postlabeling. To characterize this adduct, it was chromatographically compared with DNA adduct profiles generated in several in vitro and in vivo experimental systems. First, MCF-7 cells were exposed to a number of chemical carcino- [a,h]anthracene, 3-methylcholanthrene, and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine. Spot 1 was detected as a minor adduct in cells treated with B[a]P but not other compounds. Second, to determine whether Spot 1 is derived from lipid peroxidation products or estrogen metabolites, it was compared with adduct profiles of cells or DNAs exposed to 17␤-estradiol, 4-hydroxy estradiol, 4-hydroxynonenal, or oxidized oat oil. Spot 1 was not detectable in these samples. In addition, Spot 1 did not comigrate with the 1,N 2 -ethenodeoxyguanosine adduct standard. Third, to explore the mechanism of Spot 1 formation, it was compared with adduct profiles detected in DNA or mononucleotides reacted with BPDE, 1-OH-7,8-dihydrodiol of B[a]P, and 3-OH-7,8-dihydrodiol of B[a]P as well as in rats orally treated with B[a]P. Spot 1 comigrated with a minor adduct in BPDEtreated DNA during anion exchange rechromatography but these two adducts were separated by partition chromatography. Spot 1 also behaved in a manner that was very similar to that of the polar B[a]P adducts detected in rat liver, but the two adducts were separated by HPLC. Fourth, Spot 1 was compared with CD1 mice exposed to 7H-benzo[c]fluorene (B[c]F). Spot 1 from some patients comigrated with a major adduct induced by B[c]F. Finally, we found that the presence of Spot 1 in human breast tissues was not related to smoking status but, rather, with CYP1A1 MspI polymorphism. The CYP1A1 mutant carriers had a significantly higher frequency of this adduct than did the wild-type genotypes. Furthermore, individuals with Spot 1 had a significantly higher staining intensity for BPDE-PAH adducts in their tissue sections than those without it. These results demonstrate that this major bulky DNA adduct detected in human breast tissues is related to PAH exposure. Environ. Mol. Mutagen. 39:193-200, 2002.

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Section: Resultsmentioning

confidence: 99%

Characterization of a major aromatic DNA adduct detected in human breast tissues

Wang

Firozi

et al. 2002

Environ and Mol Mutagen

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“…For example, the dose-dependent formation of DNA adducts of the chemical may be quantifiable at levels below the range in which an increased incidence of tumors is detectable. Such data may be used to extend the doseresponse curve for tumors if there is a high degree of confidence that the formation of these adducts is a requisite step in the development of the tumors in question and will display the same dose response as the tumor data at low doses (48)(49)(50)(51). Many other biomarkers and preneoplastic changes have been reported that may be evaluated on a case-by-case basis for use in extending the dose-response curve (52)(53)(54)(55)(56)(57)(58).…”

Section: Introductionmentioning

confidence: 99%

Topics in cancer risk assessment.

Olin

Neumann

Foran

et al. 1997

Environ Health Perspect

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The estimation of carcinogenic risks from exposure to chemicals has become an integral part of the regulatory process in the United States within the past decade. With it have come considerable controversy and debate over the scientific merits and shortcomings of the methods and their impact on risk management decisions. In this paper we highlight selected topics of current interest in the debate. As an indication of the level of public concern, we note the major recent reports on risk assessment from the National Academy of Sciences and the U.S. Environmental Protection Agency's proposed substantial revisions to its Guidelines for Carcinogen Risk Assessment. We identify and briefly frame several key scientific issues in cancer risk assessment, including the growing recognition of the importance of understanding the mode of action of carcinogenesis in experimental animals and in humans, the methodologies and challenges in quantitative extrapolation of cancer risks, and the question of how to assess and account for human variability in susceptibility to carcinogens. In addition, we discuss initiatives in progress that may fundamentally alter the carcinogenesis testing paradigm.

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“…ER␣ also interacts with chromatin modifying proteins including proteins with histone acetylase activity such as the cyclic AMP response element-binding protein (CBP/p300, Refs. 15-18) and BRG1, the human homolog of the SNF2␤ subunit of the SWI2/SNF2 complex (19,20).Regions of the genome involved in active transcription are more susceptible to DNA-damaging agents, which are present in the environment and as by products of cell metabolism (21,22). DNA repair systems such as base excision repair and nucleotide excision repair are involved in repair of these DNA lesions (21,23).…”

mentioning

confidence: 99%

“…Regions of the genome involved in active transcription are more susceptible to DNA-damaging agents, which are present in the environment and as by products of cell metabolism (21,22). DNA repair systems such as base excision repair and nucleotide excision repair are involved in repair of these DNA lesions (21,23).…”

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confidence: 99%

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Interaction of Estrogen Receptor α with 3-Methyladenine DNA Glycosylase Modulates Transcription and DNA Repair

Likhite

Cass

Anderson

et al. 2004

Journal of Biological Chemistry

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Estrogen receptor ␣ (ER␣) interacts with basal transcription factors, coregulatory proteins, and chromatin modifiers to initiate transcription of the target genes. We have identified a novel interaction between ER␣ and the DNA repair protein 3-methyladenine DNA glycosylase (MPG) thereby providing a functional link between gene expression and DNA repair. Interestingly, the ER␣-MPG interaction was enhanced by the presence of estrogen response element (ERE)-containing DNA. In vitro pull-down assays indicated that the interaction of ER␣ with MPG was direct and occurred through the DNAand ligand-binding domains and the hinge region of the receptor. More importantly, endogenously expressed ER␣ and MPG from MCF-7 cells coimmunoprecipitated with ER␣-and MPG-specific antibodies. The ER␣-MPG interaction had functional consequences on the activities of both proteins. ER␣ increased MPG acetylation, stabilized the binding of MPG with hypoxanthine-containing oligos, and enhanced MPG-catalyzed removal of hypoxanthine from DNA. In turn, MPG dramatically stabilized the interaction of ER␣ with ERE-containing oligos, decreased p300-mediated acetylation of the receptor, and reduced transcription of simple and complex ERE-containing reporter plasmids in a dose-dependent manner. Our studies suggest that recruitment of MPG to ERE-containing genes influences transcription and plays a role in maintaining integrity of the genome by recruiting DNA repair proteins to actively transcribing DNA.Estrogen is critical for the growth, development, and homeostasis of neural, skeletal, cardiovascular, and reproductive tissues (1, 2). The actions of estrogen are mediated by two members of the nuclear receptor family, estrogen receptors (ERs) 1 ␣ and ␤. ER␣ is, however, generally a more potent transcriptional activator than ER␤ (3-5). Like other nuclear receptor family members, ER␣ has a modular structure. At the amino terminus is the A/B region with its autonomous activation function 1 (6). Region C encompasses the DNA binding domain and is linked by the hinge domain to region E, which contains the ligand-binding domain (LBD, Ref. 7). The DNAbinding domain has two zinc finger motifs that are involved in DNA binding. The LBD contains a hydrophobic pocket that interacts with estrogens and antiestrogens. The LBD also contains a ligand-dependent activation function 2, which is responsible for interaction of the receptor with coregulatory proteins (8 -10).ER␣ binds to estrogen response elements (EREs) in target genes to initiate changes in transcription. The consensus ERE is comprised of the palindromic sequence GGTCAnnnTGACC and is found in the Xenopus laevis vitellogenin A2 gene (11). In addition to interacting with EREs, ER␣ modulates transcription through its interaction with components of the basal transcription machinery, regulatory proteins, and chromatin modifiers (12). ER␣ interacts with proteins in the basal transcription complex including TATA-binding protein (13). The coregulatory proteins steroid receptor coactivator 1, transcription interm...

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Endogenous DNA adducts: Potential and paradox

Cited by 286 publications

References 185 publications

Characterization of a major aromatic DNA adduct detected in human breast tissues

Characterization of a major aromatic DNA adduct detected in human breast tissues

Topics in cancer risk assessment.

Interaction of Estrogen Receptor α with 3-Methyladenine DNA Glycosylase Modulates Transcription and DNA Repair

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