8-hydroxy-2--deoxyguanosine and Liver-Diseases

Inflammation of the hepatobiliary system in chronic opisthorchiasis is associated with an elevated level of urinary 8-oxo-7,8 dihydro-2'deoxyguanosine (8-oxodG) during active as well as past exposure to Opisthorchis viverrini infection. In this study, we evaluated the short-term effect of praziquantel treatment on hepatobiliary disease (HBD) using urinary 8-oxodG as an inflammatory marker in a cohort of residents in endemic areas of opisthorchiasis in Khon Kaen, Thailand. The HBD status in terms of periductal fibrosis (PDF) was determined by abdominal ultrasonography and O. viverrini infection was monitored at baseline and 2-4 weeks after curative treatment by praziquantel. Analysis of O. viverrini-infected participants who were PDF-ve revealed that there was a significant reduction of urinary 8-oxodG after treatment compared with the baseline levels (p <  0.001). By contrast, in PDF+ve individuals, the levels of urinary 8-oxodG were similar between baseline and those post-treatment. Although confirmation by using a larger sample size is needed, the positive association between HBD and urinary 8-oxodG level after worm clearance suggests that chronic hepatobiliary inflammation is neither affected nor interrupted by short-term praziquantel treatment. Individuals with persistent PDF at pre- and post-treatment who have a high risk of cholangiocarcinoma, could be identified within 2-4 weeks after parasite removal by drug treatment. Thus, urinary 8-oxodG is a useful biomarker for predicting persistent PDF in individuals with a recent drug treatment history who require further clinical investigation, management and treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anthelmintics; Biliary Tract Diseases; Biomarkers; Deoxyguanosine; Female; Humans; Liver Diseases; Male; Middle Aged; Opisthorchiasis; Praziquantel

To evaluate the urinary levels of 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to-platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p < .001). Urinary 8-oxo-Gsn was significantly associated with AST, APRI and PT (p = .013, p = .026 and p = .049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632-0.759) and 0.731 (0.672-0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Aged; Deoxyguanosine; Female; Guanosine; Hepatitis B; Hepatitis B virus; Humans; Liver Diseases; Male; Middle Aged; Oxidative Stress; RNA; Young Adult

Rats with a normal birth weight (NBW) or intra-uterine growth retardation (IUGR) were fed basic diets (NBW and IUGR groups) or basic diets supplemented with curcumin (NC and IC groups) from 6 to 12 weeks. The body weight of IUGR rats was lower (P<0·05) than that of the controls. Rats with IUGR showed higher (P<0·05) concentrations of TNF-α, IL-1β and IL-6; higher (P<0·05) activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in their serum; and increased (P<0·05) concentrations of malondialdehyde (MDA), protein carbonyl (PC) and 8-hydroxy-2'-deoxyguanosine (8-OHDG) in the liver compared with the NBW rats. The livers of IUGR rats exhibited a lower (P<0·05) superoxide dismutase activity and decreased (P<0·05) metabolic efficiency of the hepatic glutathione redox cycle compared with those of the NBW rats. In response to dietary curcumin supplementation, concentrations of inflammatory cytokines and activities of AST and ALT in the serum and MDA, PC and 8-OHDG in the liver were lower (P<0·05), and the hepatic glutathione redox cycle in the liver was improved (P<0·05) in the IC group than in the IUGR group. These results were associated with lower (P<0·05) phosphorylated levels of the NF-κB pathway and Janus kinase 2 (JAK2) and higher (P<0·05) mRNA expression of genes involved in the nuclear factor, erythroid 2-like 2 (Nfe2l2)/antioxidant response element (ARE) pathway in the liver of the IC rats than that of the IUGR rats. Maternal undernutrition decreased birth weight and led to inflammation, oxidative damage and injury in rats. Curcumin appeared to be beneficial in preventing IUGR-induced inflammation, oxidative damage and injury by activating the expression of the NF-κB, JAK/STAT and Nfe2l2/ARE pathways in the liver.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Animals; Animals, Newborn; Aspartate Aminotransferases; ATP-Binding Cassette Transporters; Birth Weight; Caenorhabditis elegans Proteins; Curcumin; Cytokines; Deoxyguanosine; Dietary Supplements; Disease Models, Animal; Female; Fetal Growth Retardation; Gene Expression; Inflammation; Liver; Liver Diseases; Oxidation-Reduction; Oxidative Stress; Pregnancy; Rats

Oxidative stress (OS) plays an important role in the progression of chronic liver disease including organ injury and hypoalbuminemia. Long-term oral supplementation with branched-chain amino acids (BCAAs) can inhibit liver dysfunction but their role in the prevention of liver fibrosis and injury to the liver is unclear. The aim of this study was to assess how BCAAs preserve liver function from OS. To investigate how BCAAs specifically prevent OS, we evaluated the effect of oral supplementation with BCAAs on OS using a rat liver cirrhosis model. Liver cirrhosis was induced in ten male Sprague-Dawley rats by administering carbon tetrachloride for 12 weeks. Five of the ten carbon tetrachloride-treated rats were assigned to a control group and five to a BCAA group. BCAA-supplementation significantly preserved plasma albumin concentrations and significantly inhibited the occurrence of organ injury as determined by blood chemistry analysis. Hepatic expression of OGG1 mRNA was increased in the BCAA group compared to the control group. In the BCAA group, increased hepatic levels of OGG1 protein were found by western blot. On the other hand, the number of 8-OHdG-positive cells was significantly higher in liver sections taken 1 month after carbon tetrachloride treatment. Furthermore, OGG1-positive cells were significantly increased in the hepatocytes around the central vein. BCAA was found to reduce OS, which could possibly lead to a decrease in the occurrence of hypoalbuminemia and organ injury. Our results indicate that BCAA-enriched nutrients stimulate antioxidant DNA repair in a rat model of liver injury induced by carbon tetrachloride.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amino Acids, Branched-Chain; Animals; Antioxidants; Biomarkers; Blotting, Western; Carbon Tetrachloride; Cytokines; Deoxyguanosine; Dietary Supplements; Disease Models, Animal; DNA Glycosylases; DNA Repair; Food; Immunohistochemistry; Liver; Liver Diseases; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley

Topical application of lipopolysaccharide and proteases to the gingival sulcus induced not only periodontal inflammation but also detectable liver changes in rats fed a normal diet. However, these changes in the liver were not sufficient to induce pathological consequences. The purpose of the present study was to investigate whether gingival inflammation-induced liver change would have more dramatic pathological consequences in rats fed a high-cholesterol diet compared with the effect of the high-cholesterol diet alone.. Twenty-four male Wistar rats were divided into four groups. During an 8 week experimental period, two groups were fed a normal diet and the other two were fed a high-cholesterol diet containing 1% cholesterol (w/w) and 0.5% cholic acid (w/w). Four weeks prior to the end of the experimental period, one of each of the dietary groups received daily topical application of lipopolysaccharide and proteases to the gingival sulcus, while the other was treated with pyrogen-free water.. In the rats without application of lipopolysaccharide and proteases, the serum level of hexanoyl-lysine, scores of steatosis and inflammation, and concentration of 8-hydroxydeoxyguanosine in liver of rats fed a high-cholesterol diet were higher than in those fed a normal diet. In rats fed a high-cholesterol diet, the scores of steatosis and inflammation and the concentration of 8-hydroxydeoxyguanosine in the liver of rats with application of lipopolysaccharide and proteases were higher than in those without.. In a rat model, application of lipopolysaccharide and proteases to the gingival sulcus augmented the effect of a high-cholesterol diet on steatosis, inflammation and oxidative damage in the liver.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Topical; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bacterial Proteins; C-Reactive Protein; Cholesterol, Dietary; Cholic Acid; Deoxyguanosine; Escherichia coli; Fatty Liver; Gingiva; Hepatitis; Lipid Peroxides; Lipopolysaccharides; Liver; Liver Diseases; Lysine; Male; Mitochondria, Liver; Peptide Hydrolases; Periodontitis; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Streptomyces griseus

Many post-operative patients with biliary atresia (BA) suffer from liver dysfunction, such as chronic inflammation even without jaundice after a Kasai's hepatic portoenterostomy.. The presence and degree of oxidative stress were evaluated in the post-operative patients with BA. Twelve outpatients who underwent a Kasai's hepatic portoenterostomy were evaluated. The active oxygen products, the rate of bioantioxidant, the markers of oxidative stress, and the degree of hepatic oxidative stress were examined by immunohistochemical staining of biopsied specimens.. All of the oxidative stress markers in the post-operative patients with BA increased in comparison to those in the controls. Moreover, 8-OHdG immunohistochemical staining was positive in 84+/-4.8% in hepatic cells in the portal area in the post-operative patients with BA.. The post-operative patients with BA were under increased oxidative stress, even if their liver dysfunction was mild without jaundice. Antioxidant therapy might be necessary to decrease of oxidative stress in the post-operative patients with BA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Biliary Atresia; Biomarkers; Case-Control Studies; Child; Child, Preschool; Collagen Type IV; Deoxyguanosine; Dinoprost; Female; gamma-Glutamyltransferase; Humans; Immunohistochemistry; Infant; Insulin-Like Growth Factor I; Liver Diseases; Male; Oxidative Stress; Portoenterostomy, Hepatic; Postoperative Period; Superoxide Dismutase

Periodontitis increases the serum lipopolysaccharide level, contributing to liver injury. Toothbrushing improves periodontitis and may also affect serum lipopolysaccharide concentration and periodontitis-induced liver injury. The purpose of the present study was to examine whether the improvement in periodontal inflammation by toothbrushing clinically affects the serum lipopolysaccharide level and hepatic pathological changes in rat periodontitis.. Thirty male Wistar rats were divided into 5 groups, 2 groups receiving topical application of pyrogen-free water to the gingival sulcus for 4 or 8 weeks. The next 2 groups received topical application of lipopolysaccharide and proteases for 4 or 8 weeks. The last group received topical application of lipopolysaccharide and proteases for 8 weeks, and the palatal gingiva was brushed with a powered toothbrush once a day for 4 weeks prior to the end of the experimental period.. Topical application of lipopolysaccharide and proteases induced not only periodontal inflammation but also an elevation in the serum lipopolysaccharide concentration, with increasing hepatic inflammation, steatosis and 8-hydroxydeoxyguanosine levels in a time-dependent manner. The rats that received gingival stimulation showed decreased polymorphonuclear leukocyte infiltration and collagen loss levels in the periodontal lesions. Furthermore, this group also showed a decrease in serum lipopolysaccharide concentration and hepatic inflammation, steatosis and 8-hydroxydeoxyguanosine levels, compared with the group receiving no treatment.. Toothbrushing promoted healing of periodontal lesions, decreased serum lipopolysaccharide concentration and suppressed liver injury in a rat periodontitis model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alveolar Bone Loss; Animals; Chemical and Drug Induced Liver Injury; Collagen; Connective Tissue; Deoxyguanosine; DNA, Mitochondrial; Epithelial Attachment; Escherichia coli; Fatty Liver; Gingiva; Leukocyte Count; Lipopolysaccharides; Liver Diseases; Male; Neutrophil Infiltration; Neutrophils; Peptide Hydrolases; Periodontal Attachment Loss; Periodontitis; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Streptomyces griseus; Toothbrushing; Tumor Necrosis Factor-alpha

Isoniazid is a widely used drug for the treatment of tuberculosis, but hepatotoxicity is a major concern during treatment. Thiopronin contains an SH-group and is generally considered an antioxidant. The aim of the present study was to investigate the effects of thiopronin during liver injury and DNA damage induced by isoniazid. Rats were injected daily with isoniazid (100 mg/kg, i.p.) for 21 days with or without thiopronin co-administration (60 mg/kg, i.p.) from day 11 to day 21. The influence of thiopronin on isoniazid-induced DNA oxidative damage was analyzed in precision-cut rat liver slices by HPLC-MS/MS. Thiopronin prevented isoniazid-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage (alanine aminotransferase and aspartate aminotransferase) and histopathological analysis. In vivo, thiopronin significantly inhibited isoniazid-induced CYP2E1 activity as assessed by both chlorzoxazone hydroxylase and aniline hydroxylase (p<0.001). Thiopronin concentration-dependently inhibited CYP2E1-dependent aniline hydroxylation, and the Dixon plots suggest that thiopronin is a competitive inhibitor of CYP2E1. Thiopronin markedly attenuated isoniazid-induced inhibition of the detoxification system through cytosolic glutathione S-transferases (GSTs), including mu GST and alpha GST. In precision-cut liver slices, the free radical scavenging activity of thiopronin reduced the generation of DNA adducts induced by isoniazid (p<0.05). Altogether, these results suggest that thiopronin exerts its hepatoprotective activity against isoniazid-induced hepatotoxicity by inhibiting the production of free radicals in addition to its role as a scavenger. Thiopronin may reduce free radical generation via inhibition of hepatic CYP2E1 and increase the removal of free radicals directly or through the induction of cytosolic GSTs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Aniline Compounds; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chlorzoxazone; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Cytoprotection; Deoxyguanosine; Disease Models, Animal; DNA Adducts; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Glutathione Transferase; Hydroxylation; Isoniazid; Kinetics; Liver; Liver Diseases; Male; Oxidative Stress; Rats; Rats, Wistar; Tiopronin

Oxidative stress is known to be involved in the pathogenesis of biliary atresia (BA), but the mechanism has yet to be elucidated. We studied 8-hydroxydeoxyguanosine (8-OHdG) and mitochondrial copy number as potential markers for oxidative stress in BA.. Hepatic immunoreactive 8-OHdG expression was investigated during the early stage of BA when the patients received Kasai portoenterostomy (KP), during the late stage when the patients received liver transplantation (LT), in patients with choledochal cyst as disease control, and in patients with histologically normal liver as normal control. Apoptosis of liver cells was examined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeling stain. The mitochondrial DNA copy number was measured by real-time polymerase chain reaction.. The number of hepatocytes positive for immunoreactive 8-OHdG was significantly increased in KP (65% +/- 18%) compared with LT (30% +/- 32%; P = 0.029) and choledochal cyst (25% +/- 20%; P = 0.037). The 8-OHdG labeling index was significantly correlated with the grade of chronic hepatitis activity (Spearman r = 0.495; P = 0.037). The hepatocyte terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeling index in KP (15% +/- 4%) was significantly higher than that in LT (5% +/- 2%; P = 0.018) and in choledochal cyst (3% +/- 2%; P = 0.010). Mitochondrial copy number was significantly less in KP than in LT (7.33 +/- 0.75 vs 8.91 +/- 1.32; P = 0.045) and in normal control (7.33 +/- 0.75 vs 9.20 +/- 1.20; P = 0.021).. The early stage of BA is associated with stronger inflammatory reaction, augmented oxidative DNA, and mitochondrial DNA damage as manifested by higher immunoreactive 8-OHdG and apoptotic activities and by a decrease in mitochondrial copy number.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Apoptosis; Biliary Atresia; Biomarkers; Child; Child, Preschool; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Infant; Liver; Liver Diseases; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Polymerase Chain Reaction; Severity of Illness Index; Statistics, Nonparametric

Excessive alcohol consumption is associated with increased risks of many diseases including cancer. We evaluated oxidative DNA damage in Aldh2 +/+ and Aldh2 -/- mice after they had been subjected to acute ethanol exposure. Olive tail moment, which was measured using a comet assay, was not increased by ethanol treatment in both Aldh2 +/+ and Aldh2 -/- mice. However, after controlling for the effect of ethanol exposure, the Aldh2 genotype was a significant determinant for Olive tail moments. Although the ethanol treatment significantly increased the hepatic 8-OHdG generation in only Aldh2 +/+ mice, the level of 8-OHdG was the highest in Aldh2 -/- ethanol treated mice. The increase in the level of 8-OHdG was associated with hepatic expression of cytochrome P450 2E1 (CYP2E1). The levels of Olive tail moment and the hepatic 8-OHdG in the Aldh2 -/- control group were significantly higher than those of the Aldh2 +/+ control group. The level of CYP2E1 in liver tissue showed a similar pattern to those of the oxidative DNA damage markers. This study shows that acute ethanol consumption increases oxidative DNA damage and that expression of CYP2E1 protein may play a pivotal role in the induction of oxidative DNA damage. The finding that oxidative DNA damage was more intense in Aldh2 -/- mice than in Aldh2 +/+ mice suggests that ALDH2-deficient individuals may be more susceptible than wild-type ALDH2 individuals to ethanol-mediated liver disease, including cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Analysis of Variance; Animals; Blotting, Western; Chemical and Drug Induced Liver Injury; Comet Assay; Cytochrome P-450 CYP2E1; Deoxyguanosine; Disease Models, Animal; DNA Damage; Ethanol; Genetic Predisposition to Disease; Liver; Liver Diseases; Male; Mice; Mice, Knockout; Microsomes, Liver; Oxidative Stress; Polymorphism, Genetic

Urinary 8-hydroxy-2'-deoxyguanosin(8-OHdG) has been reported as sensitive biomarker of oxidative DNA damage and also of oxidative stress. We measured the urinary 8-OHdG in patients with chronic liver diseases by competitive ELISA, and analyzed the relationship with clinical characteristics. Fifty patients (male/female: 22/28) with chronic liver disease were enrolled this study. The mean concentration of urinary 8-OHdG in healthy control and patients with liver cirrhosis, chronic hepatitis C, chronic hepatitis B, and autoimmune hepatitis were 10.40+/-3.14, 10.14+/-4.19, 11.79+/-5.58, 14.99+/-4.46, and 13.64+/-3.84 microg/gCr, respectively. There were no significant differences among the five group. The mean concentration of urinary 8-OHdG in inveterate drinker was significantly higher than that in non-drinker (16.67+/-4.29 vs. 11.19+/-4.80 microg/gCr, p<0.05). The smoking enhanced the elevation of urinary 8-OHdG in drinkers. In clinical characteristics, serum y-GTP, a marker of alcoholic liver disease, had significant positive correlation with urinary 8-OHdG on the drinker with chronic hepatitis. In addition, there was a positive correlation between serum ferritin levels and urinary 8-OHdG levels. Iron in the liver suggested oxidative damage of hepatocytes through the fenton reaction in patients with chronic liver disease. In conclusion, drinking and smoking induced liver damage by oxidative stress, and urinary 8-OHdG may be reliable marker of oxidative stress in patients with chronic liver disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Alcohol Drinking; Biomarkers; Chronic Disease; Deoxyguanosine; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Ferritins; gamma-Glutamyltransferase; Humans; Liver Diseases; Male; Middle Aged; Oxidative Stress; Smoking

8-Hydroxydeoxyguanosine (8-OHdG) is a promutagenic DNA lesion produced by oxygen radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress.. Hepatic expression of 8-OHdG was immunohistochemically investigated in control and diseased human livers.. While no positive immunolabeling for 8-OHdG was observed in control livers, 8-OHdG was widely evident in diseased livers. Nuclear expression of 8-OHdG in the hepatocytes and bile duct cells were found in various forms of chronic hepatitis. 8-OHdG-positive hepatocytes were especially abundant in the periportal area with piecemeal necrosis and prominent cell infiltration. The number of positive hepatocytes significantly increased with the progression of severity of chronic hepatitis activity (r(s)=0.68, P<0.05). In alcoholic liver disease, nuclear expression of 8-OHdG was detected in the hepatocytes in the area of alcoholic hepatitis. Regarding primary biliary cirrhosis, 8-OHdG was preferentially detected in the nuclei of injured bile ducts (11 of 12 cases, 91.7%) and occasionally (2 of 12 cases, 16.7%) in the nuclei of hepatocytes around the bile duct lesions.. These results indicate that oxidative DNA damage is common in various forms of chronic liver disease suggesting a possible link between chronic inflammation and hepatocarcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Bile Duct Diseases; Biomarkers; Deoxyguanosine; DNA Damage; Hepatitis; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunohistochemistry; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Diseases, Alcoholic; Middle Aged; Mitotic Index; Necrosis; Oxidation-Reduction