Oxidized apurinic/apyrimidinic sites formed in DNa by oxidative mutagens

Povirk, Lawrence F.; Steighner, Robert J.

doi:10.1016/0027-5107(89)90193-0

Cited by 46 publications

(25 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, lack of direct comparisons between the levels of depurinating adducts and AP sites weakens the hypothesis that depurinating adducts are the predominant source for AP site formation. It is known that AP sites could arise from ROS by nonspecific hydrogen atom abstraction from the C-1′, C-2′, and C-4′ positions of deoxyribose (46). Additionally, 8-oxo-dG, which is formed under these conditions, is more reactive than dG and can undergo secondary oxidation leading to destabilization of the N-glycosidic bond, and production of the aldehydic sites.…”

Section: Discussionmentioning

confidence: 99%

Redox Cycling of Catechol Estrogens Generating Apurinic/Apyrimidinic Sites and 8-oxo-Deoxyguanosine via Reactive Oxygen Species Differentiates Equine and Human Estrogens

Wang

Chandrasena

Yuan

et al. 2010

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Metabolic activation of estrogens to catechols and further oxidation to highly reactive o-quinones generates DNA damage including apurinic/apyrimidinic (AP) sites. 4-Hydroxyequilenin (4-OHEN) is the major catechol metabolite of equine estrogens present in estrogen replacement formulations, known to cause DNA strand breaks, oxidized bases, and stable and depurinating adducts. However, the direct formation of AP sites by 4-OHEN has not been characterized. In the present study, the induction of AP sites in vitro by 4-OHEN and the endogenous catechol estrogen metabolite, 4-hydroxyestrone (4-OHE) was examined by an aldehyde reactive probe assay. Both 4-OHEN and 4-OHE can significantly enhance the levels of AP sites in calf thymus DNA in the presence of the redox cycling agents, copper ion and NADPH. The B-ring unsaturated catechol 4-OHEN induced AP sites without added copper, whereas 4-OHE required copper. AP sites were also generated much more rapidly by 4-OHEN. For both catechol estrogens, the levels of AP sites correlated linearly with 8-oxo-dG levels, implying that depuriniation resulted from reactive oxygen species (ROS) rather than depurination of estrogen-DNA adducts. ROS modulators such as catalase which scavenges hydrogen peroxide and a Cu(I) chelator blocked the formation of AP sites. In MCF-7 breast cancer cells, 4-OHEN significantly enhanced the formation of AP sites with added NADH. In contrast, no significant induction of AP sites was detected in 4-OHE-treated cells. The greater redox activity of the equine catechol estrogen produces rapid oxidative DNA damage via ROS, which is enhanced by redox cycling agents and interestingly by NADPHdependent quinone oxidoreductase (NQO1).

show abstract

Section: Discussionmentioning

confidence: 99%

Redox Cycling of Catechol Estrogens Generating Apurinic/Apyrimidinic Sites and 8-oxo-Deoxyguanosine via Reactive Oxygen Species Differentiates Equine and Human Estrogens

Wang

Chandrasena

Yuan

et al. 2010

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…First, the AP site is the common lesion produced by ionizing radiation and by the radiomimetic drugs t o which AT cells are sensitive [3][4][5]171. Second, defects in several enzymes involved in the repair of AP sites have been demonstrated for some AT cell lines.…”

Section: Introductionmentioning

confidence: 99%

Mutagenesis by apurinic sites in normal and ataxia telangiectasia human lymphoblastoid cells

Klinedinst

Drinkwater

1992

Molecular Carcinogenesis

View full text Add to dashboard Cite

We used a shuttle vector based on the Epstein-Barr virus origin of plasmid replication (oriP) to determine the types of mutations induced by depurination in human cells. Plasmid DNA was incubated at pH 2 at 40 degrees C for various times to induce up to 20 apurinic (AP) sites per 9.7-kb plasmid and electroporated into lymphoblastoid cells derived from either a normal individual or an ataxia telangiectasia patient. After replication of the vector in the human cells, plasmid DNA was isolated and analyzed for mutations induced in the plasmid-encoded herpes simplex virus type 1-thymidine kinase gene. Both the frequencies and types of mutations induced by depurination were essentially identical for normal and ataxia telangiectasia cells. The mutant frequency at 20 AP sites/plasmid was 10-fold to 13-fold greater than that observed for untreated DNA. Deletion and frameshift events accounted for 46-55% of the mutants induced by depurination. The induced deletions were relatively small (median size, 100-150 bp) and characterized by short (1-5 bp) regions of sequence homology at the endpoints. These mutations and the frameshifts, a majority of which occurred in runs of identical nucleotides, are consistent with a model involving AP-site-induced template dislocation during DNA synthesis. A broad spectrum of base-substitution mutations, which accounted for 19-36% of the induced mutants, was observed. The apparent preference for insertion opposite AP sites in human cells was G (43-55%) greater than A approximately C (18-21%) greater than T (9-14%). Our results in human cells contrast markedly with those published previously for the mutational specificity of AP sites in Escherichia coli, in which a large majority of the mutants resulted from insertion of an A opposite the abasic site.

show abstract

“…rRNA and. perhaps most importantly, DNA have all been shown to suffer oxidative damage in vivo [2,30,38,[55][56][57]69], Although DNA is a relatively simple biopolymer, made up of only four dif ferent nucleic acids, its integrity is vital to cell division and survival. Oxidative altera tions to nucleic acid polymers has been shown to disrupt transcription, translation, and DNA replication, and to give rise to mutations and (ultimately) cell senescence or death [5, 33.…”

Section: Dna Repairmentioning

confidence: 99%

“…Bases undergo ring saturation, ring opening, ring contraction, and hydroxylation. These types of alteration usually re sult in a loss of aromaticity and planarity, which can cause local distortions in the dou ble helix [76], Depending on the type and extent of damage, the altered bases can be found either attached to, or dissociated from the DNA molecule to generate apurinic/apyrimidinic (AP) sites [37,55,76], Radical interactions with DNA appear to be fairly nonspecific; hence, the phosphodiester backbone may also be oxidatively damaged. Damage to the sugar and phos phate moieties, which form the backbone, may result in strand breaks [69,74], De pending on the site of radical attack, unusual 3' and 5' ends (i.e., non 3'-OH, non 5'-P04) can be generated.…”

Section: Dna Repairmentioning

confidence: 99%

Protein, Lipid and DNA Repair Systems in Oxidative Stress: The Free-Radical Theory of Aging Revisited

Pacifici

Davies²

1991

Gerontology

375

147

View full text Add to dashboard Cite

Aerobic organisms are constantly exposed to oxygen radicals and related oxidants. The antioxidant compounds and enzymes they have evolved remove most of the potentially damaging radicals/oxidants; however, damage to cellular proteins, lipids, nucleic acids and carbohydrates can be observed even under normal physiological conditions. Re-reduction of cellular components (direct repair) may be important for some biomolecules. In most cases studied to date, however, enzymatic degradation (by proteases, lipases, nucleases) appears to release damaged elements for excretion and conserve undamaged components for reutilization (indirect repair). In addition, the removal of damaged components appears to prevent or diminish the potential cytotoxicity of oxidized macromolecules. Several studies have reported an accumulation of oxidatively damaged cellular components with age (e.g., cataract formation, lipofuscin). Such reports are evidence that oxidant damage is one of several factors which contribute to the aging process, and provide at least partial support for the free-radical theory of aging. Studies of age-related changes in the activities, or levels of antioxidant enzymes and antioxidant compounds, however, have not provided complete understanding of the putative role of free radicals/oxidants in the aging process. In this review, we present the hypothesis that decreased activities or constitutive levels of oxidant repair enzymes may contribute to a progressive accumulation of oxidant damage with aging. Furthermore, the ability to mount an effective response to oxidative stress (induction of oxidant stress genes and proteins) may decline with age, thus predisposing older cells and organisms to oxidant damage.

show abstract

Oxidized apurinic/apyrimidinic sites formed in DNa by oxidative mutagens

Cited by 46 publications

References 37 publications

Redox Cycling of Catechol Estrogens Generating Apurinic/Apyrimidinic Sites and 8-oxo-Deoxyguanosine via Reactive Oxygen Species Differentiates Equine and Human Estrogens

Redox Cycling of Catechol Estrogens Generating Apurinic/Apyrimidinic Sites and 8-oxo-Deoxyguanosine via Reactive Oxygen Species Differentiates Equine and Human Estrogens

Mutagenesis by apurinic sites in normal and ataxia telangiectasia human lymphoblastoid cells

Protein, Lipid and DNA Repair Systems in Oxidative Stress: The Free-Radical Theory of Aging Revisited

Contact Info

Product

Resources

About