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PubMed2006

Prophylaxis of oxidative DNA damage by formamidopyrimidine-DNA glycosylase.

Lying at the gas-exchange interface, lung epithelia may be at risk of oxidation-induced mutagenesis. Further, inflammation processes possibly consequent on smoking liberate reactive oxygen species that multiply the carcinogenic effects of tobacco. DNA repair mechanisms play a major role in counteracting the deleterious effects of oxidative DNA damage. Some studies find positive associations between lung cancer and variations in the human 8-oxoguanine DNA glycosylase (hOGG1) gene that encodes a major DNA glycosylase for oxidized lesions with sluggish kinetics properties. The bacterial homologue formamidopyrimidine-DNA glycosylase (FPG) is 80-fold faster than hOGG1 in repairing mutagenic oxidative lesions. Cell-culture studies have shown that FPG can be expressed in mammalian cells, where it accelerates DNA repair and abates mutagenicity of a wide range of DNA-damaging agents. Prophylaxis of oxidative DNA damage and mutation could be achieved in lung epithelia and other tissues of at-risk individuals by expression of the FPG protein. Currently available vehicles for this peculiar type of gene therapy are briefly surveyed.

Adenoviridae↗
PubMed2006

Hydroxytyrosol lipophilic analogues: enzymatic synthesis, radical scavenging activity and DNA oxidative damage protection.

The olive oil phenol hydroxytyrosol (3), as well its metabolite homovanillic alcohol (4), were subjected to chemoselective lipase-catalysed acylations, affording with good yield 10 derivatives (5-14) bearing C(2), C(3), C(4), C(10) and C(18) acyl chains at C-1. Hydroxytyrosol (3) and its lipophilic derivatives showed very good DPPH. radical scavenging activity. Compounds 3, 4 and their lipophilic analogues 5-14 were subjected to the atypical Comet test on whole blood cells: 3 and its analogues 5 and 6, with little hydrophobic character (logP<or=1.20), showed a good protective effect against H(2)O(2) induced oxidative DNA damage. The homovanillic alcohol 4 and its analogues 10-14 resulted scarcely effective both as radical scavengers and antioxidant agents.

Acetylation↗
PubMed2005

Negative association between serum dioxin level and oxidative DNA damage markers in municipal waste incinerator workers.

OBJECTIVES: To investigate the effect of dioxin on the formation of oxidative DNA damage and urinary mutagenicity, we measured the concentrations of serum dioxins and lymphocytic 8-hydroxydeoxyguanosine (8-OH-dG) in 57 male waste incinerator workers, urinary 8-OH-dG and urinary mutagenicity in 29 male waste incinerator workers. METHODS: Information about the subjects was obtained from a questionnaire. Concentrations of polychlorinated dibenzo-p-dioxin (PCDD), polychlorinated dibenzofuran (PCDF), and coplanar-polychlorinated-biphenyl (Co-PCB) in serum samples from the workers were measured with a high-resolution gas chromatograph /high-resolution mass spectrometer. Lymphocytic and urinary 8-OH-dG levels were measured with a high-performance liquid chromatography-electrochemical detector system. The urinary mutagenicity was measured with umu assay. RESULTS: The lymphocytic 8-OH-dG level showed a negative association with the serum dioxin level (total value of TEQ-PCDD, PCDF, and Co-PCB). Urinary 8-OH-dG did not show correlation with serum dioxin level, but showed positive correlation with the smoking index. CONCLUSIONS: With respect to the subjects' serum dioxin level, dioxin did not increase the urinary 8-OH-dG level by oxidative DNA damage, but upregulation of the primary defenses with oxidative damage and/or DNA repair system activity might have occurred.

Adult↗
PubMed2002

Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides.

The U.S. National Toxicology Program has shown clear evidence of carcinogenicity of nickel subsulfide (Ni(3)S(2)) and some evidence of carcinogenicity of NiO (green) in rats. In the present study, DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. In cultured HeLa cells, Ni(3)S(2) induced a significant increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO (green), and NiSO(4) did not. On the other hand, in rats, intratracheal instillation of all these nickel compounds significantly increased 8-OH-dG content in the lungs. The disparities in DNA damage between cultured cells and animals could be accounted for by two different mechanisms for nickel-induced oxidative DNA damage in lungs of rats. One is direct oxidative DNA damage: Ni(II) enters the cells and then reacts with endogenous and/or nickel sulfide-produced hydrogen peroxide (H(2)O(2)) to give reactive oxygen species that cause DNA damage. This mechanism is supported by oxidative damage to isolated DNA treated with Ni(II) and H(2)O(2). The other mechanism is indirect oxidative DNA damage due to inflammation. This double mechanism for DNA damage may explain the relatively high carcinogenic risk associated with Ni(3)S(2).

Animals↗
PubMed1993

Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro and in the bone marrow in vivo.

Benzene, an important industrial chemical, is myelotoxic and leukemogenic in humans. It is metabolized by cytochrome P450 2E1 to various phenolic metabolites which accumulate in the bone marrow. Bone marrow contains high levels of myeloperoxidase which can catalyze the further metabolism of the phenolic metabolites to reactive free radical species. Redox cycling of these free radical species produces active oxygen. This active oxygen may damage cellular DNA (known as oxidative DNA damage) and induce genotoxic effects. Here we report the induction of oxidative DNA damage by benzene and its phenolic metabolites in HL60 cells in vitro and in the bone marrow of C57BL/6 x C3H F1 mice in vivo utilizing 8-hydroxy-2'-deoxyguanosine as a marker. HL60 cells (a human leukemia cell line) contain high levels of myeloperoxidase and were used as an in vitro model system. Exposure of these cells to phenol, hydroquinone, and 1,2,4-benzenetriol resulted in an increased level of oxidative DNA damage. An increase in oxidative DNA damage was also observed in the mouse bone marrow in vivo 1 h after benzene administration. A dose of 200 mg/kg benzene produced a 5-fold increase in the 8-hydroxydeoxyguanosine level. Combinations of phenol, catechol, and hydroquinone also resulted in significant increases in steady state levels of oxidative DNA damage in the mouse bone marrow but were not effective when administered individually. Administration of 1,2,4-benzenetriol alone did, however, result in a significant increase in oxidative DNA damage. This represents the first direct demonstration of active oxygen production by benzene and its phenolic metabolites in vivo. The conversion of benzene to phenolic metabolites and the subsequent production of oxidative DNA damage may therefore play a role in the benzene-induced genotoxicity, myelotoxicity, and leukemia.

Animals↗
PubMed1998

Substrate specificity of Schizosaccharomyces pombe Nth protein for products of oxidative DNA damage.

A gene from Schizosaccharomyces pombe, which encodes a protein with a strong sequence similarity to the Nth protein of Escherichia coli, has recently been identified [Roldán-Arjona, T., Anselmino, C., and Lindahl, T. (1996) Nucleic Acids Res. 24, 3307-3312]. The functional analysis of this eukaryotic enzyme indicated that it is a homologue of E. coli Nth protein. The gene has been subcloned and the protein (Nth-Spo) purified to apparent homogeneity. We investigated the substrate specificity of this eukaryotic enzyme for modified bases in oxidatively damaged DNA, using the technique of gas chromatography/isotope-dilution mass spectrometry (GC/IDMS). DNA substrates containing up to 17 types of modified bases were prepared by gamma-irradiation or by treatment with H2O2 in the presence of Fe(III)-EDTA or Cu(II). The results revealed an efficient excision of five pyrimidine-derived lesions, 5-hydroxycytosine, thymine glycol, 5-hydroxy-6-hydrothymine, 5,6-dihydroxycytosine, and 5-hydroxyuracil. None of the other pyrimidine or purine lesions was excised. Excision was measured as a function of enzyme concentration, time, substrate concentration, and temperature. Kinetic constants were determined. Although some DNA base lesions removed by Nth-Spo protein were similar to those previously described for E. coli Nth protein, differences between substrate specificities of these two enzymes were noted.

DNA Damage↗
PubMed1997

Increased oxidative DNA damage and hepatocyte overexpression of specific cytochrome P450 isoforms in hepatitis of mice infected with Helicobacter hepaticus.

A recently discovered bacterium, Helicobacter hepaticus, infects the intrahepatic bile canaliculi of mice, causing a severe chronic hepatitis culminating in liver cancer. Thus, it affords an animal model for study of bacteria-associated tumorigenesis including H. pylori-related gastric cancer. Reactive oxygen species are often postulated to contribute to this process. We now report that hepatitis of male mice infected with H. hepaticus show significant increases in the oxidatively damaged DNA deoxynucleoside 8-hydroxydeoxyguanosine, with the degree of damage increasing with progression of the disease. Perfusion of infected livers with nitro blue tetrazolium revealed that superoxide was produced in the cytoplasm of hepatocytes, especially in association with plasmacytic infiltrates near portal triads. Contrary to expectations, Kupffer cells, macrophages, and neutrophils were rarely involved. However, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in many cells, concomitant with severe hepatitis. The CYP2A5 immunohistochemical staining co-localized with formazan deposits resulting from nitro blue tetrazolium reduction and occurred in nuclei as well as cytoplasm. These findings suggest that CYP2A5 contributes to the superoxide production and 8-hydroxydeoxyguanosine formation, although reactive oxygen species from an unknown source in the hepatocytes leading to CYP2A5 induction or coincidental occurrence of these events are also possibilities. Three glutathione S-transferase isoforms, mGSTP1-1 (pi), mGSTA1-1 (YaYa), and mGSTA4-4, also showed striking increases evidencing major oxidative stress in these livers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1993

Increased formation of 8-hydroxydeoxyguanosine, an oxidative DNA damage, in lymphoblasts from Fanconi's anemia patients due to possible catalase deficiency.

Fanconi's anemia (FA) cells are highly susceptible to both reactive oxygen species and mitomycin C (MMC), a DNA cross-linking agent. In this study we have determined the amounts of 8-hydroxydeoxyguanosine (8OHdG), typical of oxidative DNA damage, in Epstein-Barr virus transformed lymphoblasts from FA patients and normal controls by the use of HPLC combined with electrochemical detection. FA cells (HSC72 and 99 cells being assigned to FA complementation group A) formed 2-3 times more 8OHdG than control cells after incubation with 20 mM H2O2 at 37 degrees C for 30 min. FA cells also formed more 8-hydroxyguanosine, typical of oxidative RNA damage, than control cells. FA cells showed decreased activity to decompose H2O2. Although the activity in FA cells was only 20-30% less than control cells, the remaining, undecomposed H2O2 concentration was almost twice as much in FA cells as in control cells, and the remaining H2O2 concentration correlated well with the amounts of 8OHdG formation. The H2O2 decomposing activity was almost completely inhibited by sodium azide (NaN3) or aminotriazole, both catalase inhibitors. With these inhibitors the amounts of 8OHdG formation were much higher than in those cells without inhibitors, and were almost the same in control cells as in FA cells. Catalase activity in FA cell lysates was 70-80% of controls. MMC also increased 8OHdG formation in FA cells only at ED100 but not at ED50. These results indicate that FA cells, at least FA complementation group A cells, have increased susceptibility to oxidative DNA damage, and that this increased susceptibility is possibly due to decreased catalase activity. These results also suggest that catalase plays an important role in protecting DNA from oxidative damage. However, this increased susceptibility to oxidative DNA damage is considered not to be the major cause of the increased susceptibility to MMC.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: protection by melatonin and related molecules.

Chromium (Cr) compounds are known occupational and environmental carcinogens. This trace element is found in the workplace primarily in the valence forms Cr(III) and Cr(VI). Cr(III), which was thought originally to be relatively nontoxic, was recently found to be more reactive toward purified DNA than was chromium(VI). Herein, we examined the ability of Cr(III) to induce oxidative DNA damage by measuring the formation of 8-hydroxydeoxyguanosine (8-OH-dG) in purified calf thymus DNA incubated with CrCl3 plus H2O2. In this system we observed that the Cr(III)-induced formation of 8-OH-dG in isolated DNA was both dose- and time-dependent. When melatonin and related molecules, including 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (pinoline), N-acetylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, were co-incubated with CrCl3 plus H2O2, the accumulations of 8-OH-dG in DNA samples were markedly inhibited in a concentration-dependent manner. The concentrations of each indole required to reduce DNA damage by 50%, i.e. the IC50 values, were 0.48, 0.51, 0.88, 1.00 and 3.08 microM for pinoline, melatonin, N-acetylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, respectively. These results suggest that one of the mechanisms by which Cr(III) may induce cancer is via Fenton-type reactions which generate the hydroxyl radical (*OH). The findings also indicate that the protective effects of melatonin and related molecules against Cr(III)-induced carcinogenesis relate to their direct *OH scavenging ability which thereby reduces the formation of the damaged DNA product, 8-OH-dG.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques.

BACKGROUND: The formation of reactive oxygen species is a critical event in atherosclerosis because it promotes cell proliferation, hypertrophy, growth arrest, and/or apoptosis and oxidation of LDL. In the present study, we investigated whether reactive oxygen species-induced oxidative damage to DNA occurs in human atherosclerotic plaques and whether this is accompanied by the upregulation of DNA repair mechanisms. METHODS AND RESULTS: We observed increased immunoreactivity against the oxidative DNA damage marker 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) in plaques of the carotid artery compared with the adjacent inner media and nonatherosclerotic mammary arteries. Strong 8-oxo-dG immunoreactivity was found in all cell types of the plaque including macrophages, smooth muscle cells, and endothelial cells. As shown by competitive ELISA, carotid plaques contained 160+/-29 8-oxo-dG residues/10(5) dG versus 3+/-1 8-oxo-dG residues/10(5) dG in mammary arteries. Single-cell gel electrophoresis showed elevated levels of DNA strand breaks in the plaque. The overall number of apoptotic nuclei was low (1% to 2%) and did not correlate with the amount of 8-oxo-dG immunoreactive cells (>90%). This suggests that initial damage to DNA occurs at a sublethal level. Several DNA repair systems that are involved in base excision repair (redox factor/AP endonuclease [Ref 1] and poly(ADP-ribose) polymerase 1 [PARP-1]) or nonspecific repair pathways (p53, DNA-dependent protein kinase) were upregulated, as shown by Western blotting and immunohistochemistry. Overexpression of DNA repair enzymes was associated with elevated levels of proliferating cell nuclear antigen. CONCLUSIONS: Our findings provide evidence that oxidative DNA damage and repair increase significantly in human atherosclerotic plaques.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

High dietary intake of sodium selenite induces oxidative DNA damage in rat liver.

One mechanism for the cancer-chemopreventive effects of high selenium (Se) intake is hypothesized to be antioxidant protection of DNA. In this work we examine DNA oxidation in whole animals as a function of dietary Se intake and carcinogen administration. Weanling male Sprague-Dawley rats were fed a basal, Torula yeast-based, Se-deficient diet supplemented with 0, 0.15, or 2.0 ppm Se as sodium selenite for 10 wk. They were then injected with 0, 0.1, or 10 mg /kg body weight of the pro-oxidant carcinogen N-nitrosodiethylamine. High levels of carcinogen and high levels of selenite intake each increased concentration of 8-hydroxy-2'-deoxyguanosine in liver DNA. Se-dependent glutathione peroxidase I gene expression and enzyme activity were dramatically reduced by dietary Se deficiency but were unaffected by carcinogen administration. There were no significant main or interactive effects of Se or carcinogen on activity or gene expression of the DNA repair enzyme 8-oxoguanine glycosylase I. These results do not support the hypothesis that high Se intake may be cancer-preventive by inhibiting oxidative DNA damage. Rather than inhibiting oxidative DNA damage, these findings suggest that high dietary intake of inorganic Se may promote in vivo DNA oxidation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor kappaB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma.

AIM: Several epidemiological studies have demonstrated a close association between Helicobacter pylori (H pylori) infection and non-cardiac carcinoma of the stomach. H pylori infection induces active inflammation with neutrophilic infiltrations as well as production of oxygen free radicals that can cause DNA damage. The DNA damage induced by oxygen free radicals could have very harmful consequences, leading to gene modifications that are potentially mutagenic and/or carcinogenic. The aims of the present study were to assess the effect of H pylori infection on the expression of inducible nitric oxidative synthase (iNOS) and the production of 8-hydroxy-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA injury in human gastric mucosa with and without tumor lesions, and to assess the possible factors affecting cell death signaling due to oxidative DNA damage. METHODS: In this study, 40 gastric carcinoma specimens and adjacent specimens were obtained from surgical resection. We determined the level of 8-OHdG formation by HPLC-ECD, and the expression of iNOS and mechanism of cell death signaling (including nuclear factor-kappaB(NFkappaB), MEKK-1, Caspase 3, B Cell lymphomal leukemia-2 (Bcl-2), inhibitor of apoptosis protein (IAP) and myeloid cell leukemia-1 (Mcl-1)) by Western-blot assay. RESULTS: The concentrations of 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP were significantly higher in cancer tissues than in adjacent non-cancer tissues. In addition, significantly higher concentrations of 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP were detected in patients infected with H pylori compared with patients who were not infected with H pylori. Furthermore, 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP concentrations were significantly higher in stage 3 and 4 patients than in stage 1 and 2 patients. CONCLUSION: Chronic H pylori infection induces iNOS expression and subsequent DNA damage as well as enhances anti-apoptosis signal transduction. This sequence of events supports the hypothesis that oxygen-free radical-mediated damage due to H pylori plays a pivotal role in the development of gastric carcinoma in patients with chronic gastritis.

Adenocarcinoma↗
PubMed2005

A half-marathon and a marathon run induce oxidative DNA damage, reduce antioxidant capacity to protect DNA against damage and modify immune function in hobby runners.

This study investigated whether a 21.1 km (half-marathon) or a 42.195 km (marathon) run modulates DNA damage, antioxidant capacity in lymphocytes and plasma, and the immune system in healthy hobby runners. Ten and 12 volunteers who completed the Baden-Marathon race in Karlsruhe with a running distance of 21.1 km and 41.195 km, respectively, were assessed 10 days before and immediately after the finish. There was no increase in the levels of endogenous DNA strand breaks immediately after half-marathon or marathon races. A statistically significant increase in the levels of oxidative DNA damage in lymphocytes was found using endonuclease III but not formamidopyrimidine glycolase (Fpg). The resistance of DNA to oxidative damage induced by hydrogen peroxide in isolated lymphocytes was significantly decreased after both races. The levels of plasma antioxidants such as alpha-tocopherol, beta-carotene and lycopene were close to, or higher than, those considered optimal for reducing the risk of cardiovascular diseases and there were no significant changes after the races in antioxidant capacity of LDL (lag-time test) or plasma in ORAC, TEAC or paraoxonase assays. The number and percentage of granulocytes and monocytes able to generate oxidative burst were significantly increased after both races, but the lytic activity of NK cells was significantly increased at the end of the half-marathon; no effect was observed in the marathon runners. Thus, oxidative DNA damage in lymphocytes, decreased the antioxidant capacity to protect lymphocytes against DNA strand breaks and increased the formation of reactive species by phagocytes in well-nourished hobby runners indicating moderate oxidative damage during such high-intensity exercise.

Adult↗
PubMed2000

Expression of the Fpg protein of Escherichia coli in Saccharomyces cerevisiae: effects on spontaneous mutagenesis and sensitivity to oxidative DNA damage.

The biological relevance of oxidative DNA damage has been unveiled by the identification of genes such as fpg of E. coli or OGG1 of Saccharomyces cerevisiae. Both Fpg and Ogg1 proteins are DNA glycosylases/AP lyases that excise 7,8-dihydro-8-oxoguanine (8-OxoG) and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (Me-FapyG) from damaged DNA. Although similar, the enzymatic and biological properties of Fpg and Ogg1 proteins are not identical. Furthermore, the Fpg and Ogg1 proteins do not show significant sequence homologies. In this study, we investigated the ability of the Fpg protein of E. coli to complement phenotypes thought to be due to oxidative DNA damage in Saccharomyces cerevisiae. To express Fpg in yeast, the coding sequence of the fpg gene was placed under the control of a strong yeast promoter in the expression vector pCM190 to generate the pFPG240 plasmid. The Ogg1-deficient yeast strain CD138, ogg1::TRP1, was transformed with pFPG240 and the expression of Fpg was measured. Expression of Fpg in yeast harboring pFPG240 was revealed by efficient release of Me-FapyG and cleavage of 8-OxoG-containing duplexes by cell free protein extracts. The production of the Fpg protein in yeast cells was further demonstrated by immunoblotting analysis using anti-Fpg antibodies. Fpg expression suppresses the spontaneous mutator phenotype of ogg1- yeast for the production of canavanin resistant mutants (CanR) and Lys+ revertants. Fpg expression also restores the capacity of plasmid DNA treated with methylene blue plus visible light (MB-light) to transform the yeast ogg1- rad1- double mutant.

Cross Reactions↗
PubMed2000

The effects of vitamin C and vitamin E on oxidative DNA damage: results from a randomized controlled trial.

Oxidative DNA damage may be important in mutagenic, carcinogenic, and aging processes. Although it is plausible that antioxidant vitamins may reduce oxidative DNA damage, evidence from human studies has been sparse and inconsistent. We determined the short-term effects of vitamin C (500 mg/day) and vitamin E (400 IU d-alpha-tocopheryl acetate/day) supplements on oxidative DNA damage in a double-masked, placebo-controlled, 2x2 factorial trial in 184 nonsmoking adults. Mean duration of supplementation was 2 months. Oxidative DNA damage was measured by 24-h urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG). At baseline, urinary 8-OHdG (mean +/- SE; ng/mg creatinine) was associated with race (15.6 +/- 0.8 in African Americans versus 20.3 +/- 1.2 in Caucasians, P = 0.001), prior antioxidant supplement use (18.6 +/- 0.8 in users versus 13.8 +/- 1.5 in non-users, P = 0.007), and regular exercise (19.2 +/- 1.1 in exercisers versus 16.6 +/- 0.9 in non-exercisers, P = 0.04). Fruit and vegetable intake and serum ascorbic acid were inversely associated with urinary 8-OHdG (P-trend = 0.02 and 0.016, respectively). The benefits of fruit and vegetable intake became evident with the consumption being at least three servings/day. At the end of supplementation, change from baseline in urinary 8-OHdG (mean +/- SE; ng/mg creatinine) was -0.6 +/- 1.4 (P = 0.61), 0.6 +/- 1.1 (P = 0.59), 0.5 +/- 1.0 (P = 0.61), and 1.6 +/- 1.4 (P = 0.27) in the placebo, vitamin C alone, vitamin E alone, and combined vitamins C and E groups, respectively. In overall and subgroup analyses, there was no significant main effect or interaction effect of the supplements on urinary 8-OHdG. In conclusion, supplementation of diet with vitamin C (500 mg/day) and vitamin E (400 IU d-alpha-tocopheryl acetate/day) had no significant main effect or interaction effect on oxidative DNA damage as measured by urinary 8-OHdG in nonsmoking adults. However, several aspects of a healthy lifestyle were associated with lower oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Detection of hepatic oxidative DNA damage in patients with hepatoblastoma and children with non-neoplastic disease.

BACKGROUND: The authors have revealed a significant association between hepatoblastoma and low birth weight. This study was done to explore the evidence that liver cells were oxidatively damaged, based on the hypothesis that oxidative damage to DNA is involved in the development of hepatoblastoma in children of low birth weight. PROCEDURE: Oxidative DNA damage in the liver was examined by immunohistochemically detecting the presence of a DNA repair product, 8-hydroxy-2'-deoxyguanosine (8-OHdG), in five patients with hepatoblastoma and 14 children with non-neoplastic disease. RESULTS: Positive staining for 8-OHdG was observed in all five patients with hepatoblastoma. Distribution of 8-OHdG positivity was diffuse in the intralobular area in one patient and was restricted to the periportal area of the lobules in four patients. There was no apparent correlation between birth weight of the patients, histological findings in the liver, and the distribution of 8-OHdG positivity. In children with non-neoplastic disease, 8-OHdG was detected in nine of 14 patients, and 8-OHdG was positive in the intralobular area of the liver parenchyma except in one patient. CONCLUSIONS: These results suggest that the cause of oxidative DNA damage in patients with hepatoblastoma may be different from the cause, extensive parenchymal damage to the liver, in children with non-neoplastic disease, but the 8-OHdG formation is not specific to hepatoblastoma patients of low birth weight. Further studies to elucidate the true reason for the high incidence of hepatoblastoma in children of low birth weight are necessary.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Cancer risk and oxidative DNA damage in man.

In living cells reactive oxygen species (ROS) are formed continuously as a consequence of metabolic and other biochemical reactions as well as external factors. Some ROS have important physiological functions. Thus, antioxidant defense systems cannot provide complete protection from noxious effects of ROS. These include oxidative damage to DNA, which experimental studies in animals and in vitro have suggested are an important factor in carcinogenesis. Despite extensive repair oxidatively modified DNA is abundant in human tissues, in particular in tumors, i.e., in terms of 1-200 modified nucleosides per 10(5) intact nucleosides. The damaged nucleosides accumulate with age in both nuclear and mitochondrial DNA. The products of repair of these lesions are excreted into the urine in amounts corresponding to a damage rate of up to 10(4) modifications in each cell every day. The most abundant of these lesions, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), is also the most mutagenic, resulting in GT transversions which are frequently found in tumor relevant genes. A series of other oxidative modifications of base and sugar residues occur frequently in DNA, but they are less well studied and their biological significance less apparent. The biomarkers for study of oxidative DNA damage in humans include urinary excretion of oxidized nucleosides and bases as repair products and modifications in DNA isolated from target tissue or surrogate cells, such as lymphocytes. These biomarkers reflect the rate of damage and the balance between the damage and repair rate, respectively. By means of biomarkers a number of important factors have been studied in humans. Ionizing radiation, a carcinogenic and pure source of ROS, induced both urinary and leukocyte biomarkers of oxidative DNA damage. Tobacco smoking, another carcinogenic source of ROS, increased the oxidative DNA damage rate by 35-50% estimated from the urinary excretion of 8-oxodG, and the level of 8-oxodG in leukocytes by 20-50%. The main endogenous source of ROS, the oxygen consumption, showed a close correlation with the 8-oxodG excretion rate although moderate exercise appeared to have no immediate effect. So far, cross-sectional study of diet composition and intervention studies, including energy restriction and antioxidant supplements, have generally failed to show an influence on the oxidative DNA modification. However, a diet rich of Brussels sprouts reduced the oxidative DNA damage rate, estimated by the urinary excretion of 8-oxodG, and the intake of vitamin C was a determinant for the level of 8-oxodG in sperm DNA. A low-fat diet reduced another marker of oxidative DNA damage in leukocytes. In patients with diseases associated with a mechanistically based increased risk of cancer, including Fanconi anemia, chronic hepatitis, cystic fibrosis, and various autoimmune diseases, the biomarker studies indicate an increased rate of oxidative DNA damage or in some instances deficient repair. Human studies support the experimentally based notion of oxidative DNA damage as an important mutagenic and apparently carcinogenic factor. However, the proof of a causal relationship in humans is still lacking. This could possibly be supported by demonstration of the rate of oxidative DNA damage as an independent risk factor for cancer in a prospective study of biobank material using a nested case control design. In addition, oxidative damage may be important for the aging process, particularly with respect to mitochondrial DNA and the pathogenesis of inflammatory diseases.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Immunological response to oxidized LDL occurs in association with oxidative DNA damage independently of serum LDL concentrations in dyslipidemic patients.

Oxidative modification of LDL induces immunogenic epitopes in the LDL molecule, and the presence of antibodies against oxidized LDL (anti-Ox-LDL) has been demonstrated in human sera. However, little is known about the clinical significance of anti-Ox-LDL. To elucidate a clinical relationship between the immunological response to oxidized LDL and cellular oxidative stress, we measured serum titers of anti-Ox-LDL in 45 unselected patients with hypercholesterolemia and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), considered a biomarker of the oxidative damage to DNA. The anti-Ox-LDL titer was not correlated with the serum LDL-C concentration, but was correlated with the 8-OHdG concentration (r = 0.300, P < 0.05) in a simple linear regression. Multiple regression analysis indicated that 8-OHdG was independently correlated with anti-Ox-LDL (r = 0.429, P < 0.05), but no other variables, including LDL-C concentrations and smoking habit, were correlated with anti-Ox-LDL. In 16 subgroup patients, the concentrations of TC, TG and LDL-C decreased and the HDL-C concentration increased after cholesterol-lowering therapy with fluvastatin. In addition, both the anti-Ox LDL titer (14.0 +/- 9.5 to 11.4 +/- 6.6 AcU/ml, P < 0.05) and the 8-OHdG concentration (1.19 +/- 0.41 to 0.85 +/- 0.43 ng/ml, P < 0.05) also decreased after fluvastatin therapy. The immunological response to LDL oxidation on vascular wall tissues or cells appear to occur in association with oxidative DNA damage. The measurement of anti-Ox-LDL may be a useful indicator for lipid-lowering therapy.

Anticholesteremic Agents↗