ACCELERATED PAPER: Formation and accumulation of DNA ethenobases in adult Sprague-Dawley rats exposed to vinyl chloride

Guichard, Yves; Ghissassi, Fatiha El; Nair, Jagadeesan; Bartsch, Helmut; Barbin, Alain

doi:10.1093/carcin/17.8.1553

Cited by 42 publications

(30 citation statements)

References 30 publications

(57 reference statements)

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“…First, although ssDNA was used as a substrate in the phage reactivation experiments, dsDNA was used in the in vitro repair reactions, and AlkB actually prefers ssDNA over dsDNA, whereas the opposite is true for hABH2 (29,35). Second, in the in vitro reactions we used an qA-containing oligonucleotide as substrate, but qC, and not qA, is the etheno lesion introduced most frequently when DNA is exposed to chloroacetaldehyde (36,37).…”

Section: Resultsmentioning

confidence: 99%

AlkB Homologue 2–Mediated Repair of Ethenoadenine Lesions in Mammalian DNA

et al. 2008

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Endogenous formation of the mutagenic DNA adduct 1,N 6 -ethenoadenine (EA) originates from lipid peroxidation. Elevated levels of EA in cancer-prone tissues suggest a role for this adduct in the development of some cancers. The base excision repair pathway has been considered the principal repair system for EA lesions until recently, when it was shown that the Escherichia coli AlkB dioxygenase could directly reverse the damage. We report here kinetic analysis of the recombinant human AlkB homologue 2 (hABH2), which is able to repair EA lesions in DNA. Furthermore, cation exchange chromatography of nuclear extracts from wild-type and mABH2 À/À mice indicates that mABH2 is the principal dioxygenase for EA repair in vivo. This is further substantiated by experiments showing that hABH2, but not hABH3, is able to complement the E. coli alkB mutant with respect to its defective repair of etheno adducts. We conclude that ABH2 is active in the direct reversal of EA lesions, and that ABH2, together with the alkyl-N-adenine-DNA glycosylase, which is the most effective enzyme for the repair of EA, comprise the cellular defense against EA lesions. [Cancer Res 2008;68(11):4142-9]

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Section: Resultsmentioning

confidence: 99%

AlkB Homologue 2–Mediated Repair of Ethenoadenine Lesions in Mammalian DNA

et al. 2008

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“…edA adducts in mouse liver cell nuclei were randomly distributed in all cell types as demonstrated by immunohistochemistry in rescued mice. LPO-derived etheno-DNA adducts are strong promutagenic lesions and are thought to play a role in the onset of human liver cancer, induced by vinyl chloride, 46 alcohol abuse 22 and hemochromatosis. 47 The high and statistically significant increased levels of edA and edC in the urine of b-Thal/Hb E patients and in the livers of thalassemic mice indicate elevated oxidative stress and LPO-induced DNA damages in vivo that may contribute to the onset of hepatocellular carcinoma in thalassemia patients.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of lipid peroxidation‐derived DNA lesions in iron‐overloaded thalassemic mouse livers: Comparison with levels in the lymphocytes of thalassemia patients

Meerang¹,

Nair²,

Sirankapracha³

et al. 2009

Intl Journal of Cancer

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In thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of b-Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. edA, edC and M 1 dG residues were quantified by 32 P-postlabeling-TLC/ HPLC. M 1 dG levels in lymphocyte DNA from patients were 4 times as high as in controls, while the increase in edA and edC was not significant. Adducted DNA accumulated in the liver of thalassemic mice having >2.7 mg Fe/g tissue dry weight; DNA adducts and iron were highly correlated. edA was not specifically generated in certain mouse liver cell types as revealed by immunohistochemical staining. We found elevated LPO-induced DNA damage in the liver of thalassemic mouse and in lymphocytes, implicating that massive DNA damage occurs in the liver of thalassemia patients. We conclude that promutagenic LPO-derived DNA lesions are involved in the onset of hepatocellular carcinoma in these patients. ' 2009 UICC Key words: iron overload; lipid peroxidation; thalassemia; etheno-DNA adducts Iron overload, one of the major causes of morbidity and mortality in thalassemia patients, results from multiple, life-long transfusions and enhanced iron absorption as a response to increased erythropoiesis. [1][2][3] Iron overload in these patients is indicated by significantly increased levels of serum ferritin, saturated transferrin (the iron carrier protein) 4 and iron deposition in many organs. 5,6 Administration of the iron chelators, desferrioxamine and deferiprone, is commonly used in therapy. These drugs can cause serious side effects and are expensive. For desferrioxamine, a special infusion equipment is needed and, therefore, not all patients can benefit from iron-chelating therapy. In addition, patients who receive iron chelators still encounter a milder or shorter period of iron overload. As a result of iron overload, high levels of plasma iron in the form of nontransferrin bound iron (NTBI) can be found in both transfusion-dependent and transfusion-independent thalassemia patients. 7 NTBI plays a crucial role in the production of hydroxyl radicals (HO • ) in vivo that occurs through the biological Fenton-type and Haber-Weiss reactions. The resulting hydroxyl radicals can induce oxidative stress and, as a consequence, damage of cellular nucleic acids, proteins, lipids and carbohydrates, which in turn can potentiate tissue damage. 8 Previous studies demonstrated increased oxidative stress in thalassemia patients, including increased antioxidant enzyme activities and decreased nonenzymatic antioxidants. 9-12 Moreover, increase in modified DNA bases such as 8-oxodG, resulting from direct attack of hydroxyl radical to DNA, 13 increase in ortho-and meta-tyrosine, which are products of hydroxyl radical attack on phenylalanine, 14 and increase in lipid peroxidation (LPO) products, such as malondialdehyde (MDA) 10 and F 2 -isoprostane, 15 have been reported.LPO end-products such as 4-hydroxy-2-nonenal (HNE) and 1...

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“…Highly variable background levels ofcA and -C were found in all the tissues examined (132,133). After exposure of rats to VC, significantly elevated levels of sA and EC were measured in most tissues, except the brain; there were also no significant increases of EA levels in the kidney and spleen (121,134).…”

Section: Vc Initiation Of Hepatocarcinogenesismentioning

confidence: 99%