Characterization of 2‘-Deoxyadenosine Adducts Derived from 4-Oxo-2-nonenal, a Novel Product of Lipid Peroxidation

Lee, Seon Hwa; Rindgen, Diane; Bible, Roy H.; Hajdu, Elisabeth; Blair, Ian A.

doi:10.1021/tx000057z

Cited by 106 publications

(105 citation statements)

References 26 publications

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“…Their bifunctionality arises since the aldehydic group can form Schiff's bases with the ε-amino group of lysines, and the α,β-unsaturated aldehyde can act as a Michael acceptor. 4-HNE and 4-oxo-2-nonenal can also form highly mutagenic etheno-and heptano-etheno-DNA adducts, respectively [32][33][34]. To limit their potential toxicity a number of enzyme systems exist to detoxify 4-HNE (e.g.…”

Section: Detoxication Of Lipid Aldehydesmentioning

confidence: 99%

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Penning

Drury

2007

Archives of Biochemistry and Biophysics

243

211

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Aldo-Keto Reductases (AKRs) are a superfamily of NAD(P)H linked oxidoreductases that are generally monomeric 34-37 kDa proteins present in all phyla. The superfamily consists of 15 families, which contains 151 members (www.med.upenn.edu/akr). Thirteen human AKRs exist that use endogenous substrates (sugar and lipid aldehydes, prostaglandins, retinals and steroid hormones), and in many instances they regulate nuclear receptor signaling. Exogenous substrates include metabolites implicated in chemical carcinogenesis: NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), polycyclic aromatic hydrocarbon trans-dihydrodiols, and aflatoxin dialdehyde. Promoter analysis of the human genes identifies common elements involved in their regulation which include osmotic response elements, antioxidant response elements, xenobiotic response elements, AP-1 sites and steroid response elements. The human AKRs are highly polymorphic, and in some instances single nucleotide polymorphisms (SNPs) of high penetrance exist. This suggests that there will be inter-individual variation in endogenous and xenobiotic metabolism which in turn affect susceptibility to nuclear receptor signaling and chemical carcinogenesis.

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Section: Detoxication Of Lipid Aldehydesmentioning

confidence: 99%

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Penning

Drury

2007

Archives of Biochemistry and Biophysics

243

211

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“…Granulocytes and lymphocytes can generate at least four types of genotoxic or mutagenic products, namely H 2 O 2 , nitric oxide, malondialdehyde and 4-hydroxy-2,3-nonenal [155,[200][201][202][203][204][205][206][207][208][209][210][211][212][213][214][215]. H 2 O 2 can function as a progenitor of ROS like the highly reactive hydroxyl radical [196,197,216].…”

Section: Oxidative Stress-mediated Carcinogenesismentioning

confidence: 99%

Oxidant metabolism in chronic obstructive pulmonary disease

2003

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The development and progression of chronic obstructive pulmonary disease (COPD) have been associated with increased oxidative stress or reduced antioxidant resources. Several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products and degraded proteins, are indeed elevated in COPD patients. As a result, the antioxidant capacity decreases in COPD patients.The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect.COPD is linked to weight loss and in particular to loss in fat-free mass by skeletal muscle wasting. This systemic effect can be mediated by both oxidative stress and oxidative stress-mediated processes like apoptosis and inflammation. Furthermore, COPD is a predisposition for lung cancer through several mechanisms including oxidative stress and oxidative stress-mediated processes such as inflammation and disruption of genomic integrity.Current therapeutic interventions against the far-reaching consequences of the systemic oxidative stress in chronic obstructive pulmonary disease are not yet optimised. A diet designed to reduce chronic metabolic stress might form an effective therapeutic strategy in chronic obstructive pulmonary disease.

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“…Heptanone-etheno-dC (H-⑀dC) 2 (Fig. 1) is one of the substituted etheno-base DNA adducts generated by 4-oxo-2(E)-nonenal, a bifunctional electrophilic lipid peroxidation product derived from both arachidonic acid and linoleic acid (5)(6)(7)(8). This adduct, as well as H-⑀dG, serves as a biomarker of lipid peroxidation-mediated DNA damage (5).…”

mentioning

confidence: 99%

Two Distinct Translesion Synthesis Pathways across a Lipid Peroxidation-derived DNA Adduct in Mammalian Cells

Yang

Hashimoto

Wind

et al. 2009

Journal of Biological Chemistry

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Translesion DNA synthesis (TLS) of damaged DNA templates is catalyzed by specialized DNA polymerases. To probe the cellular TLS mechanism, a host-vector system consisting of mouse fibroblasts and a replicating plasmid bearing a single DNA adduct was developed. This system was used to explore the TLS mechanism of a heptanone-etheno-dC (H-⑀dC) adduct, an endogenous lesion produced by lipid peroxidation. In wild-type cells, H-⑀dC almost exclusively directed incorporation of dT and dA. Whereas knockout of the Y family TLS polymerase genes, Polh, Polk, or Poli, did not qualitatively affect these TLS events, inactivation of the Rev3 gene coding for a subunit of polymerase or of the Rev1 gene abolished TLS associated with dA, but not dT, insertion. The analysis of results of the cellular studies and in vitro TLS studies using purified polymerases has revealed that the insertion of dA and dT was catalyzed by different polymerases in cells. While insertion of dT can be catalyzed by polymerase , , and , insertion of dA is catalyzed by an unidentified polymerase that cannot catalyze extension from the resulting dA terminus. Therefore, the extension from this terminus requires the activity of polymerase -REV1. These results provide new insight into how cells use different TLS pathways to overcome a synthesis block.Endogenous reactive chemicals such as reactive oxygen species and certain lipid peroxidation products are thought to contribute significantly to aging, age-related degenerative diseases, and cancer (1-4). Cellular DNA is one of their targets, and replication of un-repaired DNA damage introduces mutations into the genome, thereby contributing to the aforementioned biological effects. Heptanone-etheno-dC (H-⑀dC) 2 (Fig. 1) is one of the substituted etheno-base DNA adducts generated by 4-oxo-2(E)-nonenal, a bifunctional electrophilic lipid peroxidation product derived from both arachidonic acid and linoleic acid (5-8). This adduct, as well as H-⑀dG, serves as a biomarker of lipid peroxidation-mediated DNA damage (5). H-⑀dC and H-⑀dG were both found in the DNA of polyps from a cyclooxygenase-2 up-regulated Min mouse, a colorectal cancer mouse model (9). Our previous study has shown that H-⑀dC blocks DNA synthesis and highly miscodes in human cells (10), raising the possibility that cyclooxygenase-2-mediated lipid peroxidation contributes to colorectal carcinogenesis in Min mice through the formation of DNA adducts. Due to its strong genotoxicity and physiological significance, H-⑀dC is an attractive DNA lesion for the mechanistic study of mammalian translesion DNA synthesis (TLS).Recently, it was revealed that various specialized DNA polymerases are actively engaged in DNA synthesis across a DNA lesion (11,12). The catalytic sites of these polymerases are much more spacious than those of replicative polymerases so that they can accommodate a modified template base and an incoming nucleotide (13-15). Accordingly, their fidelity of DNA synthesis is compromised on undamaged template DNA (16 -19). These specialized polyme...

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Characterization of 2‘-Deoxyadenosine Adducts Derived from 4-Oxo-2-nonenal, a Novel Product of Lipid Peroxidation

Cited by 106 publications

References 26 publications

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Human aldo–keto reductases: Function, gene regulation, and single nucleotide polymorphisms

Oxidant metabolism in chronic obstructive pulmonary disease

Two Distinct Translesion Synthesis Pathways across a Lipid Peroxidation-derived DNA Adduct in Mammalian Cells

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