8-hydroxy-2--deoxyguanosine and Alcoholism

A patient with liver failure due to chronic and acute alcohol abuse under consideration for an urgent liver transplant shortly after stopping alcohol may have residual abnormalities that threaten transplant success, particularly for a small graft. To address this, we studied a model in which reduced-size (50%) Lewis rat livers are transplanted into green fluorescence protein transgenic Lewis recipients after they are fed alcohol or a control diet for 5 weeks. Here we show that normal small Lewis grafts transplanted to alcohol-fed Lewis hosts developed fibrosis, whereas no fibrosis was observed in control-fed recipients. Host-derived CD133 + 8-hydroxy-2'-deoxyguanosine (8-OHdG) cells were significantly increased in livers recovered from both alcohol-fed and control recipients, but only alcohol-fed recipients demonstrated co-staining (a marker of oxidative DNA damage). α smooth muscle actin (α-SMA) staining, a marker for myofibroblasts, also co-localized with CD133 + cells only in the livers of alcohol-fed recipients. Immunostaining and polymerase chain reaction analysis confirmed that chronic alcohol consumption decreased the proportion of bone marrow stem cells (BMSCs) expressing CD133, c-Kit, and chemokine (C-X-C motif) receptor 4 markers and caused oxidative mitochondria DNA (mtDNA) damage. Culture of CD133 + cells from normal rats with medium containing 3% ethanol for 48 hours resulted in elevated mitochondrial 8-OHdG and mtDNA deletion, and ethanol exposure diminished CD133 expression but dramatically increased α-SMA expression. In conclusion, oxidative mtDNA damage and deletions occur in BMSCs of chronic alcohol-fed recipients, and these damaged cells mobilize to the small liver grafts and become myofibroblasts where they play a key role in the subsequent development of fibrosis. Liver Transplantation 23 1564-1576 2017 AASLD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute-On-Chronic Liver Failure; Alcoholism; Allografts; Animals; Bone Marrow Cells; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA, Mitochondrial; Ethanol; Fibrosis; Hepatitis, Alcoholic; Humans; Liver; Liver Transplantation; Mitochondria; Myofibroblasts; Rats; Rats, Inbred Lew; Stem Cells; Transplantation, Isogeneic

Chronic and excessive alcohol consumption increases oxidative stress. We previously found that levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, are elevated in alcohol-dependent patients without delirium tremens (DTs). The aim of this study was to compare serum 8-OHdG levels between alcohol-dependent patients with and without DTs.. We recruited 16 alcohol-dependent patients with DTs (DTs group) and 58 patients without DTs (non-DTs group). Alcohol withdrawal severity was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Serum levels of 8-OHdG and other biological indices were assayed at baseline and after 1 week of detoxification.. The mean 8-OHdG level in the DTs group was significantly higher than that in the non-DTs group (0.50 vs. 0.34 ng/ml, p < 0.001). A significant correlation was found between the highest CIWA-Ar-C scores and serum 8-OHdG levels (β = 0.43, p = 0.001) in the non-DTs group, but not in the DTs group (β = 0.34, p = 0.19). An area under receiver operating characteristic curve of 0.83 suggests that 8-OHdG levels potentially differentiate patients with DTs from those without DTs. After dividing the patients into quartiles by 8-OHdG level, we found that compared to the patients in the third and fourth quartiles, the patients in the highest quartile had an odds ratio of 24.1 (p < 0.001) to have DTs, while those in the second highest quartile had an odds ratio of 3.5 (p = 0.19). Serum 8-OHdG levels did not significantly change after 1 week of detoxification in either group.. Alcohol-dependent patients with DTs have higher serum 8-OHdG levels than those without DTs, suggesting that higher oxidative stress carries a greater risk of the occurrence of DTs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Alcohol Withdrawal Delirium; Alcoholics; Alcoholism; Biomarkers; Comorbidity; Deoxyguanosine; DNA Damage; Female; Humans; Male; Middle Aged; Oxidative Stress; Risk Factors

Chronic and excessive alcohol consumption enhances the formation of reactive oxygen species (ROS) and ethanol-derived free radicals. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a marker to estimate ROS-induced DNA damage. The study objective was to compare serum 8-OHdG levels between patients with alcohol dependence and healthy controls and to investigate the correlation between this marker and the severity of alcohol withdrawal syndrome (AWS).. We recruited 79 patients with alcohol dependence and 63 healthy control subjects. The severity of AWS was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Levels of 8-OHdG, malondialdehyde (MDA), and other biologic indexes were assayed at baseline for patient and control groups, and after 1-week detoxification for the patient group.. The 8-OHdG and MDA levels in the alcoholic group were significantly higher than those in the control group (0.34 vs. 0.27 ng/ml and 13.5 vs. 10.1 μM, respectively). Both 8-OHdG and MDA were significantly correlated with the highest CIWA-Ar-C (correlation coefficient = 0.39, p < 0.001 and 0.26, p = 0.02, respectively). In linear regression analysis, only 8-OHdG level was significantly correlated with the highest CIWA-Ar, but not MDA level (regression coefficient beta = 0.33, p = 0.003 and 0.17, p = 0.12, respectively). MDA, but not 8-OHdG levels, significantly decreased after 1 week of detoxification.. These results indicate that our alcohol-dependent individuals are vulnerable to excessive production of free radicals. Notably, the oxidative DNA damage persisted after 1-week detoxification. The AWS severity was correlated with the increase in oxidative stress, particularly the 8-OHdG levels. The impact of sustained abstinence in alcoholic patients needs to be investigated in future studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Alcoholism; Deoxyguanosine; DNA Damage; Female; Humans; Liver Function Tests; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Psychiatric Status Rating Scales; Reactive Oxygen Species; Severity of Illness Index; Substance Withdrawal Syndrome; Young Adult

It is still difficult to define the biochemical mechanisms that cause alterations in neuronal function and plasticity and neuronal cell loss in the brains of alcohol-dependent patients.. To evaluate the extent of cerebral alcohol-induced oxidative stress ex vivo, we investigated the levels of glutathione (GSH), its oxidation product glutathione disulfide (GSSG, produced by GSH-peroxidases), and the activities of catalase and superoxide dismutases (SOD). In addition, selected brain regions from up to 22 subjects (versus controls) were studied post mortem to compare the amount of oxidized DNA-base 8-hydroxy-2'-deoxyguanosine (8-OHdG) with levels of deoxyguanosine (dG) in mitochondrial and nuclear DNA.. The most prominent findings showed significantly decreased GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in the corpus mamillare and cerebellum, which appeared due to an increase in GSSG caused by chronic alcohol intake. Catalase activity was increased in only the frontal cortex, whereas decreased catalase activity was found in the corpus callosum. In contrast, neither copper-zinc-superoxide dismutase (CuZnSOD) and manganese-superoxide dismutase (MnSOD) activities nor 8-OHdG/dG molar ratios were altered, although a tendency toward higher OHdG/dG ratios in temporal and parietal cortex from alcohol-dependent patients could be detected when mitochondrial DNA was analyzed selectively.. We propose that decreased brain GSH/(GSH+2GSSG) molar redox (oxidation-reduction) ratios in alcohol-dependent patients may reflect neural impairment due to increased peroxide production after chronic alcohol consumption. However, future experiments, investigating the activities of enzymes and cofactors involved in GSH synthesis and metabolism in the human brain, will have to validate the specificity of these results for oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Alcoholism; Brain; Catalase; Deoxyguanosine; DNA, Mitochondrial; Female; Glutathione; Glutathione Disulfide; Humans; Male; Middle Aged; Oxidative Stress; Statistics, Nonparametric; Superoxide Dismutase