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PubMed2000

Crystallization and preliminary X-ray crystallographic studies of Thermus thermophilus HB8 MutM protein involved in repairs of oxidative DNA damage.

MutM protein, which removes the oxidatively damaged DNA base product, 8-oxoguanine (GO), has been crystallized by means of a hanging-drop vapor-diffusion procedure using polyethyleneglycol monomethylether 2000 as a precipitant in 2-(cyclohexylamino) ethanesulfonic acid (CHES) buffer, pH 9.8. The diffraction data derived from oscillation photographs indicate that the crystals belong to the monoclinic system and space group P2(1). The crystals have unit-cell dimensions of a = 45.4 A, b = 62.0 A, c = 99.7 A, and beta = 90.8 degrees. Assuming that the asymmetric unit contains two molecules, the Vm value was calculated to be 2.35 A(3).Da(-1). The crystals diffracted X-rays to at least 2.1 A resolution and were suitable for high-resolution X-ray crystal structure determination.

Crystallization↗
PubMed1998

Measurement of oxidative DNA damage by gas chromatography-mass spectrometry: ethanethiol prevents artifactual generation of oxidized DNA bases.

Analysis of oxidative damage to DNA bases by GC-MS enables identification of a range of base oxidation products, but requires a derivatization procedure. However, derivatization at high temperature in the presence of air can cause 'artifactual' oxidation of some undamaged bases, leading to an overestimation of their oxidation products, including 8-hydroxyguanine. Therefore derivatization conditions that could minimize this problem were investigated. Decreasing derivatization temperature to 23 degrees C lowered levels of 8-hydroxyguanine, 8-hydroxyadenine, 5-hydroxycytosine and 5-(hydroxymethyl)uracil measured by GC-MS in hydrolysed calf thymus DNA. Addition of the reducing agent ethanethiol (5%, v/v) to DNA samples during trimethylsilylation at 90 degrees C also decreased levels of these four oxidized DNA bases as well as 5-hydroxyuracil. Removal of guanine from hydrolysed DNA samples by treatment with guanase, prior to derivatization, resulted in 8-hydroxyguanine levels (54-59 pmol/mg of DNA) that were significantly lower than samples not pretreated with guanase, independent of the derivatization conditions used. Only hydrolysed DNA samples that were derivatized at 23 degrees C in the presence of ethanethiol produced 8-hydroxyguanine levels (56+/-8 pmol/mg of DNA) that were as low as those of guanase-pretreated samples. Levels of other oxidized bases were similar to samples derivatized at 23 degrees C without ethanethiol, except for 5-hydroxycytosine and 5-hydroxyuracil, which were further decreased by ethanethiol. Levels of 8-hydroxyguanine, 8-hydroxyadenine and 5-hydroxycytosine measured in hydrolysed calf thymus DNA by the improved procedures described here were comparable with those reported previously by HPLC with electrochemical detection and by GC-MS with prepurification to remove undamaged base. We conclude that artifactual oxidation of DNA bases during derivatization can be prevented by decreasing the temperature to 23 degrees C, removing air from the derivatization reaction and adding ethanethiol.

Adenine↗
PubMed2002

Time course assessment of methylmercury effects on C6 glioma cells: submicromolar concentrations induce oxidative DNA damage and apoptosis.

Organic mercury is a well-known neurotoxicant although its mechanism of action has not been fully clarified. In addition to a direct effect on neurons, much experimental evidence supports an involvement of the glial component. We assessed methylmercury hydroxide (MeHgOH) toxicity in a glial model, C6 glioma cells, exposed in the 10(-5)-10(-8) M range. The time course of the effects was studied by time-lapse confocal microscopy and supplemented with biochemical data. We have monitored cell viability and proliferation rate, reactive oxygen species (ROS), mitochondrial transmembrane potential, DNA oxidation, energetic metabolism and modalities of cell death. The earliest effect was a measurable ROS generation followed by oxidative DNA damage paralleled by a partial mitochondrial depolarization. The effect on cell viability was dose dependent. TUNEL, caspase activity and real-time morphological observation of calcein-loaded cells showed that apoptosis was the only detectable mode of cell death within this concentration range. N-acetyl-cysteine (NAC) or reduced glutathione (GSH) completely prevent the apoptotic effect of MeHgOH. The lowest effective MeHgOH concentration was 10(-7) M for ROS and DNA OH-adducts generation. The effect of submicromolar concentrations of MeHgOH on C6 cells could be relevant in the developmental neurotoxicity caused by low dose, long-term exposures, such as those of food origin. In addition, we have shown that the same concentrations are effective in the induction of DNA oxidative damage, with further potential pathogenetic implications.

8-Hydroxy-2'-Deoxyguanosine↗
PubMedDate not supplied

Accumulation of 8-oxo-2'-deoxyguanosine (as a biomarker of oxidative DNA damage) in the tissues of aged hamsters and change in antioxidant enzyme activities after single administration of N-nitrosobis(2-oxopropyl) amine.

BACKGROUND: It has been reported that DNA oxidative damage accumulates with age. Two reasons for this phenomenon are the decline in the antioxidant system and the decline in the repair system. It is not clear which of these is the main reason. OBJECTIVE: To study whether the decline in antioxidant enzyme activities causes the accumulation of DNA oxidative damage, an experimental study was performed with hamsters. METHODS: Seventy-four female Syrian golden hamsters were divided into 2 groups: a young group (28 hamsters), and an aged group (46 hamsters). The hamsters in the aged group were kept in our laboratory until they were 18 months old. The levels of 8-oxo-2'-deoxyguanosine (8-oxodG) and the activities of antioxidant enzymes, i.e. catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx), were measured in both groups. Furthermore, the same parameters were measured in the pancreas and liver following administration of N-nitrosobis(2-oxopropyl)amine (BOP), an inducer of oxidative stress in the hamster pancreas. RESULTS: In the mid brain, cerebellum, lung, heart, spleen and kidney, the 8-oxodG contents in aged hamsters were significantly higher than those in young hamsters. GPx activity decreased with age in the lung, liver and kidney, whereas SOD activity increased in the lung and liver but decreased in the kidney of aged animals. Catalase activity increased in the cerebrum, heart, pancreas and kidney but decreased in the lung and spleen of aged hamsters. When the pancreatic levels of 8-oxodG and antioxidant enzymes were measured after BOP administration, there was no clear-cut relation between the changes in those levels. CONCLUSIONS: From these results the increase in 8-oxodG contents in aged hamsters does not seem to be related to the antioxidant system but rather to a possible decline in the repair system against oxidative damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Oxidative DNA damage in tissues of pregnant female mice and fetuses caused by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces the promutagenic oxidative-damage DNA lesion, 8-oxo-2'-deoxyguanosine (8-oxo-dG), in adult animals. To investigate whether this alteration occurs in DNA after transplacental exposure, pregnant Swiss mice were administered single or multiple doses of NNK. The 8-oxo-dG was quantified in placenta, and maternal and fetal tissues. In maternal lungs, single and multiple doses of NNK significantly increased levels of 8-oxo-dG by 23% and 32%, respectively. In maternal liver, a significant 38% increase was observed after multiple dose treatment. In the fetuses, a significant 45% increase in 8-oxo-dG levels was observed in liver after multiple doses of NNK. This is the first demonstration of oxidative DNA damage after transplacental exposure to NNK, and supports the concept of maternal smoking as a contributor to the development of childhood cancer.

Animals↗
PubMed1994

Binding of anti-DNA antibodies to oxidatively damaged DNA in spouses and relatives of patients with systemic lupus erythematosus.

The prevalence of serum anti-DNA antibodies was evaluated by ELISA using oxidatively damaged DNA as antigen in 21 patients with systemic lupus erythematosus (SLE), in 9 spouses and in 15 first-degree relatives. These were compared with 12 healthy controls. There was no significant difference in the levels of serum antibodies detected between the group of spouses and normal controls with all results within the normal range of the assay. Binding of serum antibodies to the oxidatively damaged DNA was detectable in 12 (80%) of the relatives studied, and the range of values obtained overlapped significantly with the SLE patient group. The relevance of these antibodies to the immunopathology of SLE is unclear since they appear to be present in the absence of any clinical symptoms. However, they may be useful predictively as a marker for those individuals who are more likely to develop SLE.

Adolescent↗
PubMed2006

Severe oxidatively damaged DNA after cisplatin treatment of cancer patients.

There is growing evidence suggesting that cytotoxic activity of cisplatin is closely associated with increased generation of reactive oxygen species (ROS). Therefore, this study was undertaken to examine oxidative DNA damage, which arises as a result of chemotherapy with cisplatin. Using HPLC prepurification/isotope dilution GC/MS methodology, we examined the amount of 8-oxoGua and 8-oxodG excreted into urine in cancer patients (n = 66) who received chemotherapy with cisplatin. One day after the infusion of the drug, significant increase in the amount of 8-oxoGua and 8-oxodG in urine of the patients was observed, when compared to the initial value (78%, p < 0.0001 and 22%, p = 0.0051). In the "nadir days" (when the most distinct cell death based on hematological cell counts can be observed), the level of modified base and nucleoside decreased in comparison with the aforementioned time point. These results, for the first time, indicate that oxidatively damaged DNA may be, at least in part, responsible for cisplatin induced cytotoxicity. Our results also demonstrate that cell death does not contribute to urinary 8-oxoGua and 8-oxodG in humans.

Antineoplastic Agents↗
PubMed1998

Oxidative DNA damage in mouse heart, liver, and lung tissue due to acute side-stream tobacco smoke exposure.

Environmental tobacco smoke (ETS) is a hotly debated social, political, and scientific issue, pitting smokers' rights against the health and safety of nonsmokers. Striking an acceptable balance between the two depends largely on the potential health hazard assessment of ETS. Studies from this laboratory have shown that exposure to side-stream cigarette smoke (SSS), the major component of ETS, significantly increases oxidative stress in mouse heart, liver, and lung tissues. This study measures the level of oxidative damage to mouse liver, lung, and heart DNA as a result of this oxidative stress. Adult female Balb/c mice were exposed to a regimen consisting of sequences of a 30-min exposure followed by a 90-min nonexposure. This regimen was performed once for the single exposure and repeated three times for the triple exposure. The heart, lung, and liver were excised from the mice, and DNA was extracted and analyzed for the presence of the oxidative product 8-hydroxy-2'-deoxyguanosine (8-OHdG). In all three tissues, the exposure increased the presence of 8-OHdG above the control levels. In some instances, the increased levels returned to normal by the end of the nonexposure period, while other tissues showed a further increase following nonexposure. These studies demonstrate that limited exposure to SSS produces measurable DNA oxidative damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

The effects of nitroxide radicals on oxidative DNA damage.

The indolinonic and quinolinic aromatic nitroxides synthesized by us are a novel class of biological antioxidants, which afford a good degree of protection against free radical-induced oxidation in different lipid and protein systems. To further our understanding of their antioxidant behavior, we thought it essential to have more information on their effects on DNA exposed to free radicals. Here, we report on the results obtained after exposure of plasmid DNA and calf thymus DNA to peroxyl radicals generated by the water-soluble radical initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH), and the protective effects of the aromatic nitroxides and their hydroxylamines, using a simple in vitro assay for DNA damage. In addition, we also tested for the potential of these nitroxides to inhibit hydroxyl radical-mediated DNA damage inflicted by Fenton-type reactions using copper and iron ions. The commercial aliphatic nitroxides 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), and bis(2,2, 6,6-tetramethyl-1-oxyl-piperidin-4-yl)sebacate (TINUVIN 770) were included for comparison. The results show that the majority of compounds tested protect: (i) both plasmid DNA and calf thymus DNA against AAPH-mediated oxidative damage in a concentration-dependent fashion (1-0.1 mM), (ii) both Fe(II) and Cu(I) induced DNA oxidative damage. However, all compounds failed to protect DNA against damage inflicted by the presence of the transition metals in combination with H(2)O(2). The differences in protection between the compounds are discussed in relation to their molecular structure and chemical reactivity.

Amidines↗
PubMed2006

Dietary antioxidants and beneficial effect on oxidatively damaged DNA.

Many biomonitoring studies have investigated the role of antioxidants in reducing oxidatively generated DNA damage in urine and white blood cells. A collective interpretation is difficult because many studies lack sufficient control and have unreasonably high baseline levels of oxidatively damaged DNA. In a survey of this antioxidant hypothesis, we identified 139 cross-sectional and intervention studies. Restricted selection criteria with exclusion of studies having suboptimal design or unreasonably high baseline damage level provided 85 eligible studies for analysis. Ten of the 27 cross-sectional studies reported negative correlations between antioxidants and oxidatively damaged DNA, albeit with correlation coefficients explaining less than 20% of the variance. Sixty-two intervention studies reported mixed results, which did not depend on sample size or duration of the intervention. Reduced levels of oxidatively damaged DNA in white blood cells and urine were reported in far more studies than expected by chance alone. Supplementation with antioxidant-rich foods was more effective than that with single antioxidants in lowering urinary excretion of oxidatively damage DNA. In conclusion, this survey indicates that ingestion of antioxidants may be associated with reduced level of DNA damage in white blood cells and urine of humans, albeit the effect is lower than previously expected.

Animals↗
PubMed1998

Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours.

The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT-PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no significant difference was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identified a single base substitution in each of the three cases: two transversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type profile. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.

Carcinoma, Small Cell↗
PubMed2003

Oxidative DNA damage following exposure to dimethylarsinous iodide: the formation of cis-thymine glycol.

The purpose of the present study was to elucidate the genotoxic mechanism of trivalent dimethylated arsenic, particularly the induction mechanism of oxidative stress in nuclear bases. Cis-thymine glycol was used as a biomarker of DNA oxidation damage. The treatment of thymine with dimethylarsinous iodide (DMI), a model compound of dimethylarsinous acid, induced the formation of cis-thymine glycol. This oxidative damage was induced via the production of dimethylated arsenic peroxide, but not via the production of superoxide anion or hydrogen peroxide. Trivalent dimethylated arsenic may thus play an important role in arsenic carcinogenesis through the induction of oxidative base damage.

Cacodylic Acid↗
PubMed1994

Role of oxidative DNA damage in the mechanism of fecapentaene-12 genotoxicity.

Fecapentaene-12 (FP-12), a fecal unsaturated, ether-linked lipid excreted by most human individuals in Western populations, has been found to be a potent genotoxin in mammalian cells. Its mechanism of genotoxicity may be mediated by oxygen radical-induced DNA damage or by direct DNA alkylation, of which the relative importance remains to be determined. In the present study, induction of oxidative genetic damage by FP-12 has been investigated, in combination with the biological inactivation of single-stranded bacteriophage phi X-174 DNA. It was shown that formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG), a marker for oxidative DNA damage, is induced dose dependently by FP-12 in 2'-deoxyguanosine (dG). It was demonstrated by application of radical scavengers that production of both the superoxide anion and singlet oxygen may be involved in the induction of 8-oxodG. The effect of OH radical scavenging appeared to be less pronounced. Enzymatic peroxidation of FP-12, which has been demonstrated to stimulate oxygen radical formation, was found to increase the hydroxylation ratio in dG, an effect which was less pronounced in single-stranded DNA and even absent in double-stranded DNA. No induction of 8-oxodG was observed after exposure of human skin fibroblasts to 60 microM FP-12 for 3 h in vitro. It was concluded that the induction of 8-oxodG by FP-12 is determined by the accessibility of the guanine molecule rather than the rate of oxygen radical formation. Although free radical formation is known to be stimulated by enzymatic peroxidation of FP-12, the inactivation of phi X-174 DNA spontaneously induced by FP-12 was found to be reduced by application of peroxidases. This furthermore demonstrates that the increased formation of reactive oxygen species by enzymatic peroxidation of FP-12 does not directly relate to increased induction of genotoxic effects. The fact that addition of radical scavengers shows limited effects on the inactivation of phi X-174 DNA suggests that the contribution of oxidative DNA damage to the genotoxic potential of FP-12 is only of minor importance.

Animals↗
PubMed2000

Effect of thyroid hormones on mitochondrial oxygen free radical production and DNA oxidative damage in the rat heart.

Mitochondria seem to be involved in oxygen radical damage and aging. However, the possible relationships between oxygen consumption and oxygen radical production by functional mitochondria, and oxidative DNA damage, have not been studied previously. In order to analyze these relationships, male Wistar rats of 12 weeks of age were rendered hyper- and hypothyroid by chronic T(3) and 6-n-propyl-2-thiouracil treatments, respectively. Hypothyroidism decreased heart mitochondrial H(2)O(2) production in States 4 (to 51% of controls; P<0.05) and 3 (to 21% of controls; P<0.05). In agreement with this, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) decreased in the heart genomic DNA of hypothyroid animals to 40% of controls (P<0.001). Studies with respiratory inhibitors showed that the decrease in oxygen radical generation observed in hypothyroidism occurred at Complex III (mainly) and at Complex I; that decrease was due to the presence of a lower free radical leak in the respiratory chain (P<0.05). Hyperthyroidism did not significantly change heart mitochondrial H(2)O(2) production since the increase in State 4 oxygen consumption in comparison with control and hypothyroid animals (P<0.05) was compensated by a decrease in the free radical leak in relation to control animals (P<0.05). In agreement with this, heart 8-oxodG was not changed in hyperthyroid animals. The lack of increase in H(2)O(2) production per unit of mitochondrial protein will protect mitochondria themselves against self-inflicted damage during hyperthyroidism.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

DNA oxidative damage in leukocytes correlates with the severity of HCV-related liver disease: validation in an open population study.

BACKGROUND/AIMS: Oxidative DNA damage, identifiable in the formation of 8-hydroxydeoxyguanosine (8-OHdG), is relevant in the mutagenesis/carcinogenesis process. The aim of this study was to assess 8-OHdG levels in patients with hepatitis C virus (HCV) infection in relation to extent of liver damage and HCV genotype. METHODS: 8-OHdG levels were measured in DNA from circulating leukocytes of 110 anti-HCV positive subjects belonging to the population of the Dionysos study, subgrouped in: 50 anti-HCV+ with persistently normal ALT, 48 with chronic hepatitis and 12 with cirrhosis. Twenty normal subjects served as Controls. 8-OHdG levels were assayed by HPLC/electrochemical detector. RESULTS: 8-OHdG levels rose (P < 0.00001) from Controls to HCV+; chronic hepatitis and cirrhosis were associated with a further increase (P < 0.02 versus HCV+). Genotype 1 was associated with higher levels of 8-OHdG (P < 0.04). Multiple logistic regression analysis showed that, after correction for potential confoundings, 8-OHdG levels correlated (P < 0.02) with presence and extent of liver damage. CONCLUSIONS: An accumulation of 8-OHdG in circulating leukocytes is a reliable marker of the extent of liver damage in HCV+ patients and is present in particular in genotype 1 infection. This genomic damage may contribute to liver carcinogenesis by causing persistent DNA changes.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Substrate specificity of Fpg protein. Recognition and cleavage of oxidatively damaged DNA.

The 8-oxoguanine-DNA glycosylase of Escherichia coli, also known as formamidopyrimidine-DNA glycosylase (Fpg protein), has N-glycosylase and AP-lyase activities. This enzyme repairs oxidative DNA damage by efficiently removing formamidopyrimidine lesions and 8-oxoguanine residues from DNA. Defined oligodeoxynucleotides containing various 8-oxopurines were used to examine the substrate specificity of Fpg protein and to establish the role of functional groups in DNA on damage recognition and catalysis. Binding affinities of Fpg protein were established for duplex oligodeoxynucleotides containing 8-oxo-2'-deoxyguanine, 8-oxo-2'-deoxyadenine, 8-oxo-2'-deoxynebularine, 8-oxo-2'-deoxyinosine, abasic sites, and a ring-open adduct of C8-aminofluorene guanine. The C8 keto group of 8-oxodG:dC presents in the major groove and is correlated with tight binding (Kd = 8.9 nM). Binding is much weaker when the C8 keto functional group is in the minor groove, as in 8-oxodG:dA (Kd = 340 nM). Km and Vmax were determined for the cleavage reaction. Specificity constants (Kcat/Km) are consistently higher for oligodeoxynucleotide duplexes containing 8-oxopurines with C6 and C8 keto groups, as in 8-oxodG:dC and 8-oxodI:dC, where Kcat/Km are 9.3 and 18 min-1 nM x 10(-3), respectively. 8-oxodN:dC lacks the C6 keto group; the specificity constant is 0.024 min-1 nM x 10(-3). Taken together, our data suggest that the C8 keto group of 8-oxodeoxyguanine and the carbonyl moiety of formamidopyrimidine enable Fpg protein to recognize and bind duplex DNA containing these modified bases. An enzyme-catalyzed reaction involving the C6 keto group of the substrate leads to removal of these lesions. A mechanism involving protonation at O-6 of 8-oxoguanine is proposed to account for the N-glycosylase activity of this enzyme.

Catalysis↗
PubMed1995

Transcription factor NF-kappa B is activated by photosensitization generating oxidative DNA damages.

Reactive oxygen intermediates like hydrogen peroxide (H2O2) have been shown to serve as messengers in the induction of NF-kappa B and, then, in the activation and replication of human immunodeficiency virus (HIV)-1 in human cells. Because H2O2 can be converted into the highly reactive OH. at various locations inside the cells, we started to investigate the generation of Reactive oxygen intermediates by photosensitization. This technique is based on the use of a photosensitizer which is a molecule absorbing visible light and which can be located at various sites inside the cell depending on its physicochemical properties. In this work, we used proflavine (PF), a cationic molecule having a high affinity for DNA, capable of intercalating between DNA base pairs. Upon visible light irradiation, intercalated PF molecules oxidize guanine residues and generate DNA single-strand breaks. In lymphocytes or monocytes latently infected with HIV-1 (ACH-2 or U1, respectively), this photosensitizing treatment induced a cytotoxicity, an induction of NF-kappa B, and a reactivation of HIV-1 in cells surviving the treatment. NF-kappa B induction by PF-mediated photosensitization was not affected by the presence of N-acetyl-L-cysteine while strong inhibition was recorded when the induction was triggered by H2O2 or by phorbol 12-myristate 13-acetate. Another transcription factor like AP-1 is less activated by this photosensitizing treatment. In comparison with other inducing treatments, such as phorbol 12-myristate 13-acetate or tumor necrosis factor alpha, the activation of NF-kappa B is slow, being optimal 120 min after treatment. These kinetic data were obtained by following, on the same samples, both the appearance of NF-kappa B in the nucleus and the disappearance of I kappa B-alpha in cytoplasmic extracts. These data allow us to postulate that signaling events, initiated by DNA oxidative damages, are transmitted into the cytoplasm where the inactive NF-kappa B factor is resident and allow the translocation of p50/p65 subunits of NF-kappa B to the nucleus leading to HIV-1 gene expression.

Acetylcysteine↗
PubMed2004

Differential effects of Helicobacter pylori eradication on oxidative DNA damage at the gastroesophageal junction and at the gastric antrum.

BACKGROUND AND AIM: Helicobacter pylori-associated gastritis causes accumulation of reactive oxygen species in the mucosal compartment. This prospective study evaluates DNA oxidative damage in biopsy samples obtained from both the antrum and the gastroesophageal junction (GEJ) before and after H. pylori eradication. PATIENTS AND METHODS: Thirty-two consecutive H. pylori-positive patients underwent endoscopy with multiple biopsy sampling (i.e., antrum, incisura angularis, fundus, and cardia at the GEJ). After H. pylori eradication, 32 patients underwent a checkup endoscopy (mean interval, 5.7 months); in a subgroup of 13 subjects, a third endoscopy procedure was also performed (mean interval, 18 months). Additional biopsy samples (two from the antrum and two from the GEJ) were used to assess 8-hydroxydeoxyguanosine (8OHdG) levels using both high-pressure liquid chromatography with electrochemical detector and ELISA. RESULTS: In the antral compartment, no significant modifications of 8OHdG levels were assessed after H. pylori eradication. Conversely, following eradication, 8OHdG levels significantly increased (high-pressure liquid chromatography with electrochemical detector, P = 0.04; ELISA method, P = 0.05) in biopsy samples taken from the GEJ, and a further increase was documented in the subgroup of patients who underwent a third endoscopy (P = 0.01). The increasing trend was more relevant in patients in whom H. pylori-cagA-positive strains were eradicated and in those affected by hiatal hernia. CONCLUSIONS: The levels of DNA adducts in the antral mucosa are not modified by H. pylori eradication; conversely, H. pylori eradication significantly increases the oxidative adducts at the GEJ. The clinical and biological importance of this situation and whether and how it relates to a higher risk of precancerous lesions is open to debate.

Anti-Ulcer Agents↗