A diet high in linoleic acid (an ω-6 PUFA) increased the formation of miscoding etheno (ε)--DNA adducts in WBC-DNA of women, but not in men (Nair et al., Cancer Epidemiol Biomark Prev 1997;6:597-601). This gender specificity could result from an interaction between ω-6 PUFA intake and estrogen catabolism, via redox-cycling of 4-hydroxyestradiol (4-OH-E(2) ) and subsequent lipid peroxidation (LPO).
View Article and Find Full Text PDFMethylation of cytidine at dCpdG sequences regulates gene expression and is altered in many chronic inflammatory diseases. Inflammation generates lipid peroxidation (LPO) products which can react with deoxycytidine, deoxyadenosine, and deoxyguanosine in DNA to form pro-mutagenic exocyclic etheno-nucleoside residues. Since 5-methyl-2'-deoxycytidine (5mdC) residues exhibit increased nucleophilicity at N3, they should be even better targets for LPO products.
View Article and Find Full Text PDFBackground: Oxidative stress enhances lipid peroxidation (LPO), which both are implicated in the promotion and progression stages of carcinogenesis, in particular under conditions of chronic inflammation and infections. Exocyclic etheno-DNA adducts, which are formed by LPO-products such as 4-hydroxy -2-nonenal, are strongly pro-mutagenic DNA lesions.
Methods: The development of ultra-sensitive detection methods for etheno-adducts in human tissues, white blood cells( WBC) and urine has provided evidence that these adducts are elevated in affected organs of cancer-prone patients, probably acting as a driving force to malignancy.
Tobacco smoke contains many alkylating agents that can react with DNA to produce O(4)-ethylthymidine (O(4)-etT) and several other types of promutagenic base modifications. Our aims were (i) to confirm results of a pilot study (Godschalk, R., Nair, J.
View Article and Find Full Text PDFExocyclic etheno-DNA adducts are formed by the reaction of lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE) with DNA bases to yield 1,N (6)-etheno-2'-deoxyadenosine (εdA), 3,-N (4)-etheno-2'-deoxycytidine (εdC), and etheno-2'-deoxyguanosine. These adducts act as a driving force for many human malignancies and are elevated in the organs of cancer-prone patients suffering from chronic inflammation and infections. Here, we describe the ultrasensitive and specific techniques for the detection of εdA and εdC in tissue and white blood cell (WBC) DNA.
View Article and Find Full Text PDFChronic infection by the liver fluke Opisthorchis viverrini is a strong risk factor for cholangiocarcinoma. To clarify the involvement of oxidative stress and lipid peroxidation-derived DNA damage, etheno (epsilon)-DNA adducts (epsilondA, epsilondC) in WBC and plasma alpha-tocopherol were measured in samples collected from O. viverrini-infected Thai patients (n = 50) and healthy noninfected volunteers (n = 20).
View Article and Find Full Text PDFChronic inflammatory processes induce oxidative and nitrative stress that trigger lipid peroxidation (LPO), whereby DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE) are generated. Miscoding etheno-modified DNA adducts including 1,N(6)-etheno-2'-deoxyadenosine (epsilondA) are formed by reaction of HNE with DNA-bases which are excreted in urine, following elimination from tissue DNA. An ultrasensitive and specific immunoprecipitation/HPLC-fluorescence detection method was developed for quantifying epsilondA excreted in urine.
View Article and Find Full Text PDFUnlabelled: Oxidative stress is thought to play a major role in the pathogenesis of hepatocellular cancer (HCC), a frequent complication of alcoholic liver disease (ALD). However, the underlying mechanisms are poorly understood. In hepatocytes of ALD patients, we recently detected by immunohistochemistry significantly increased levels of carcinogenic etheno-DNA adducts that are formed by the reaction of the major lipid peroxidation product, 4-hydroxynonenal (4-HNE) with nucleobases.
View Article and Find Full Text PDFIn thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of beta-Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. epsilondA, epsilondC and M(1)dG residues were quantified by (32)P-postlabeling-TLC/HPLC.
View Article and Find Full Text PDFChronic infection by Opisthorchis viverrini (OV) is a strong risk factor for developing cholangiocarcinoma (CCA). To clarify the involvement of oxidative stress and lipid peroxidation (LPO)-derived DNA damage, the excretion of LPO-derived etheno DNA adducts was measured in urine samples collected from healthy volunteers and OV-infected Thai subjects. 1,N(6)-etheno-2'-deoxyadenosine (epsilondA) and 3,N(4)-etheno-2'-deoxycytidine (epsilondC) levels were quantified by immunoprecipitation/high-performance liquid chromatography/fluorescence detection and (32)P-postlabeling TLC.
View Article and Find Full Text PDFObjective: Oxidative DNA damage is believed to be involved in tumor formation and may be an important biomarker for malignant transition or relapse. A decrease of such damage has been observed in human and animal studies following dietary intervention and/or changes in lifestyle such as physical exercise at different levels of intensity. The purpose of this study was to carry out a clinical trial comparing the effects of a short-term (2 weeks) exercise program of moderate intensity (0.
View Article and Find Full Text PDFThalassemic diseases including homozygous beta-thalassemia and beta-thalassemia/Hb E (beta-Thal/Hb E) are prevalent in Southeast Asia. Iron overload is a common complication in beta-thalassemia patients which induces intracellular oxidative stress and lipid peroxidation (LPO). LPO end products generate miscoding etheno adducts in DNA which after their repair are excreted in urine.
View Article and Find Full Text PDFPersistent oxidative stress and excess lipid peroxidation (LPO), induced by inflammatory processes, impaired metal storage, and/or dietary imbalance, cause accumulations and massive DNA damage. This massive DNA damage, along with deregulation of cell homeostasis, leads to malignant diseases. Reactive aldehydes produced by LPO, such as 4-hydroxy-2-nonenal, malondialdehyde, acrolein, and crotonaldehyde, react directly with DNA bases or generate bifunctional intermediates which form exocyclic DNA adducts.
View Article and Find Full Text PDFIntake of linoleic acid (LA) increased etheno-DNA adducts induced by lipid peroxidation (LPO) in white blood cells (WBC) of female but not of male volunteers [J. Nair, C.E.
View Article and Find Full Text PDFIncreased oxidative stress and subsequent lipid peroxidation (LPO) are thought to be critical events in the formation of atherosclerotic lesions in apolipoprotein E deficient mice (ApoE-KO). LPO derived reactive aldehydes react with DNA to form exocyclic etheno-DNA adducts. These pro-mutagenic DNA lesions are known to be involved in the initiation of carcinogenesis, but their role in the development of atherosclerosis is unknown.
View Article and Find Full Text PDFAtherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N(6)-ethenodeoxyadenine (varepsilondA) and 3,N(4)-ethenodeoxycytosine (varepsilondC).
View Article and Find Full Text PDFBackground And Aims: Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products.
View Article and Find Full Text PDFChronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease.
View Article and Find Full Text PDFThe goal of this study was to determine whether short-term fasting changes in urinary biomarkers related to oxidative stress: malondialdehyde (MDA), 8-isoprostaglandin F2alpha (8-isoPGF), 8-hydroxydeoxy-guanosine (8-OHdG) and 1,N6-ethenodeoxyadenosine (epsilondA) among female volunteers participating in the short-term fasting program in South Korea. The study subjects were 52 healthy women (mean age 28, range 15-48 years old) who provided urine samples both before and after the fasting program (average 7.2, range: 3-11 days).
View Article and Find Full Text PDFBiochem Biophys Res Commun
October 2005
Reactive oxygen species (ROS) and lipid peroxidation (LPO) play a role in aging and degenerative diseases. To correlate oxidative stress and LPO-derived DNA damage, we determined etheno-DNA-adducts in liver and brain from ROS overproducing OXYS rats in comparison with age-matched Wistar rats. Liver DNA samples from 3- and 15-month-old OXYS and Wistar rats were analyzed for 1,N6-ethenodeoxyadenosine (epsilondA) and 3,N4-ethenodeoxycytidine (epsilondC) by immunoaffinity/32P-postlabelling.
View Article and Find Full Text PDFChronic inflammatory processes produce an excess of ROS and DNA-reactive aldehydes from lipid peroxidation (LPO), such as trans-4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), which can modify cellular macromolecules and drive to malignancy. Etheno-modified DNA bases are generated inter alia by reaction of DNA with the major LPO product, HNE. We are investigating steady-state levels of etheno-DNA adducts in organs with diseases related to persistent inflammatory processes that can lead to malignancies.
View Article and Find Full Text PDFLong-Evans Cinnamon (LEC) rats, a model for human Wilson's disease, develop chronic hepatitis and liver tumors owing to accumulation of copper and induced oxidative stress. Lipid peroxidation (LPO)-induced etheno-DNA adducts in nuclear- and mitochondrial-DNA along with apoptosis was measured in LEC rat liver. Levels of etheno-DNA adducts (1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytidine) increased with age reaching a peak at 8 and 12 weeks in nuclear and mitochondrial DNA, respectively.
View Article and Find Full Text PDFUnlabelled: During chronic inflammatory processes an excess of free radicals and DNA-reactive aldehydes from lipid peroxidation (LPO) are produced, which deregulate cellular homeostasis and can drive normal cells to malignancy. Etheno (epsilon)-modified DNA bases are generated by reactions of DNA with a major LPO product, trans-4-hydroxy-2-nonenal. We investigated steady state levels of epsilon-DNA adducts in organs, blood or urine from patients with cancer prone diseases, especially when related to persistent inflammatory processes.
View Article and Find Full Text PDFIn south-east Asia, Taiwan and Papua New Guinea, smoking, alcohol consumption and chewing of betel quid with or without tobacco or areca nut with or without tobacco are the predominant causes of oral cancer. In most areas, betel quid consists of a mixture of areca nut, slaked lime, catechu and several condiments according to taste, wrapped in a betel leaf. Almost all habitual chewers use tobacco with or without the betel quid.
View Article and Find Full Text PDFThe malondialdehyde-modified DNA adduct, 3-(2-deoxy-beta-d-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10(3H)one (M1dG) has been detected in human tissues and is considered to be a promising biomarker for estimating lipid peroxidation-induced DNA damage. With the aim to analyze the M1dG in small amounts of DNA (<10 microg) and to improve the sensitivity, we have developed an immuno-enriched 32P-postlabeling HPLC method. The main modifications included the following steps: (i) an optimization of the immunoenrichment conditions using a monoclonal antibody (MAb D 10A1), (ii) a single labeling step of the purified M1dG 3'-monophosphate to its 5'-monophosphate at pH 6.
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