4,5-Epoxy-2(E)-decenal-Induced Formation of 1,N6-Etheno-2‘-deoxyadenosine and 1,N2-Etheno-2‘-deoxyguanosine Adducts

Lee, Seon Hwa; Oe, Tomoyuki; Blair, Ian A.

doi:10.1021/tx010147j

Cited by 77 publications

(93 citation statements)

References 26 publications

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“…8-Oxo-dG appears to be stable, and recent reports have demonstrated the presence of another endogenous adduct, ethenodeoxyadenosine, and its nucleobase in urine (32). However, a growing number of endogenous adducts have been formed in in vitro experiments that contain an exocyclic ring that blocks the Watson-Crick base-pairing region (33)(34)(35)(36). It will be important to determine the metabolic fate of these lesions as part of any attempt to develop convenient biomarkers suitable for clinical or population-based studies.…”

Section: Discussionmentioning

confidence: 99%

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Otteneder¹,

Knutson²,

Daniels³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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3-(2-Deoxy-␤-D-erythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M1dG) is a DNA adduct arising from the reaction of 2-deoxyguanosine with the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M 1dG is mutagenic in bacteria and mammalian cells and is present in the genomic DNA of healthy human beings. It is also detectable, albeit at low levels, in the urine of healthy individuals, which may make it a useful biomarker of DNA damage linked to oxidative stress. We investigated the possibility that the low urinary levels of M 1dG reflect metabolic conversion to derivatives. M 1dG was rapidly removed from plasma (t1/2 ‫؍‬ 10 min) after i.v. administration to rats. A single urinary metabolite was detected that was identified as 6-oxo-M 1dG by MS, NMR spectroscopy, and independent chemical synthesis. 6-Oxo-M1dG was generated in vitro by incubation of M 1dG with rat liver cytosols, and studies with inhibitors suggested that xanthine oxidase and aldehyde oxidase are involved in the oxidative metabolism. M1dG also was metabolized by three separate human liver cytosol preparations, indicating 6-oxo-M1dG is a likely metabolite in humans. This represents a report of the oxidative metabolism of an endogenous DNA adduct and raises the possibility that other endogenous DNA adducts are metabolized by oxidative pathways. 6-Oxo-M1dG may be a useful biomarker of endogenous DNA damage associated with inflammation, oxidative stress, and certain types of cancer chemotherapy.excretion ͉ inflammation ͉ DNA damage ͉ oxidation ͉ metabolite D NA damage from endogenous sources is believed to contribute significantly to human genetic diseases, including cancer (1, 2). A major cause of endogenous DNA damage is oxidation (3, 4). Agents such as hydroxyl radical or peroxynitrous acid oxidize nucleic acid bases or the deoxyribose backbone to form miscoding lesions or induce strand breaks (5). In addition, oxidation of other cellular constituents (i.e., lipid, protein) generates reactive derivatives that form adducts with nucleic acid bases (1). In the absence of repair, this panoply of damage results in mutations, triggers signaling to arrest cell division, or induces apoptosis.3-(2-Deoxy-␤-D-er ythro-pentofuranosyl)pyrimido[1,2-␣]purin-10(3H)-one (M 1 dG) is an adduct found at varying levels in genomic DNA of rodents and humans (6-8). It is derived from the lipid oxidation product, malondialdehyde, or the DNA oxidation product, base propenal (Scheme 1) (9-11). M 1 dG is miscoding when assayed by in vitro DNA replication and is mutagenic in bacterial and mammalian cells (12)(13)(14). It induces base pair substitutions (M 1 dG3T and M 1 dG3A) and frameshift mutations in reiterated sequences (e.g., CG n ) when shuttle vectors containing a site-specific lesion are replicated in COS-7 cells (14). Genetic and biochemical experiments indicate that M 1 dG is removed by nucleotide excision repair in both bacterial and mammalian cells (13-15).As a prerequisite for preclinical, clinical, and populationbased ...

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Section: Discussionmentioning

confidence: 99%

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

Otteneder¹,

Knutson²,

Daniels³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to abasic sites, exocyclic DNA adducts, such as ethano-bases are strong topoisomerase II poisons [177,179]. These adducts are generated following peroxidation of cellular lipids or by exposure of cells to industrial chemicals such as vinyl chloride [183,184].…”

Section: Dna Lesions As Topoisomerase II Poisonsmentioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

359

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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“…One pathway leads to the formation of 4,5-epoxy-2(E)-decenal (EDE) via α-cleavage of an alkoxy radical (3). The second is thought to involve a Hock rearrangement to form 4-hydroperoxy-2(E)-nonenal (HPNE), which is the precursor to 4-oxo-2(E)-nonenal (ONE) and 4-hydroxy-2(E)-nonenal (HNE) (4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Covalent Adducts Arising from the Decomposition Products of Lipid Hydroperoxides in the Presence of Cytochrome c

Williams

Wishnok

Tannenbaum

2007

Chem. Res. Toxicol.

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Polyunsaturated fatty acids can be converted to lipid hydroperoxides through non-enzymatic and enzymatic pathways. The prototypic ω-6 lipid hydroperoxide 13-hydroperoxy-octadecadienoic acid (13-HPODE) decomposes homolytically to form highly reactiveα,β-unsaturated aldehydes, such as 9,12-dioxo-10(E)-dodecenoic acid (DODE), 4-oxo-2(E)-nonenal (ONE), 4,5-epoxy-2(E)-decenal (EDE), and 4-hydroxy-2(E)-nonenal (HNE), that can form covalent adducts with DNA. Both 4-oxo-2 (E)-nonenal and 4-hydroxy-2(E)-nonenal can also modify proteins to form products that can potentially serve as biomarkers of lipid hydroperoxide-mediated macromolecule damage. In this study cytochrome C was used to identify and characterize the modification sites individually for each of these aldehydes and also to determine the most abundant adduct formed following decomposition of 13-HPODE. The adducts were characterized by ESI-TOF/MS analysis of the intact proteins and by a combination of ESI-ion-trap/MS n and quadrupole-TOF/MS/MS analysis of the tryptic and chymotryptic peptides.

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4,5-Epoxy-2(E)-decenal-Induced Formation of 1,N⁶-Etheno-2‘-deoxyadenosine and 1,N²-Etheno-2‘-deoxyguanosine Adducts

Cited by 77 publications

References 26 publications

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

DNA topoisomerase II, genotoxicity, and cancer

Covalent Adducts Arising from the Decomposition Products of Lipid Hydroperoxides in the Presence of Cytochrome c

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4,5-Epoxy-2(E)-decenal-Induced Formation of 1,N6-Etheno-2‘-deoxyadenosine and 1,N2-Etheno-2‘-deoxyguanosine Adducts

Cited by 77 publications

References 26 publications

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M 1 dG

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M 1 dG

DNA topoisomerase II, genotoxicity, and cancer

Covalent Adducts Arising from the Decomposition Products of Lipid Hydroperoxides in the Presence of Cytochrome c

Contact Info

Product

Resources

About

4,5-Epoxy-2(E)-decenal-Induced Formation of 1,N⁶-Etheno-2‘-deoxyadenosine and 1,N²-Etheno-2‘-deoxyguanosine Adducts

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG

In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M ₁ dG