8-hydroxy-2--deoxyguanosine and HIV-Infections

Oxidative damage DNA is aninevitable, natural consequence of cellular metabolism resulting from formation of reactive oxygen species (ROS) including free oxygen radicals. However, the level ofthe damage may increase under conditions of oxidative stress, arising from exposure to a variety of physical or chemical insults. In this review we present the mechanisms by which oxidative damage to DNA may lead to pathological processes involved in the development of cancer, cardiovascular diseases and ageing. Furthermore, we describe mechanisms of DNA repair which play a key role in maintaining cellular function upon DNA insult. Among over 20 identified and described oxidative modifications of DNA bases only one derivative, namely 8-oxo-2'-deoxyguanosine (8-oxo-dG), has become a subject of intense research. Therefore, we are presenting methods of 8-oxo-dG detection as a marker of oxidatively damaged DNA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Autoimmune Diseases; Biomarkers; Deoxyguanosine; DNA Damage; DNA Repair; Hepatitis B; HIV Infections; Humans; Inflammation; Mass Spectrometry; Neoplasms; Oxidative Stress; Reactive Oxygen Species

Human immunodeficiency virus (HIV)-infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside-enriched American ginseng extract 200 mg twice daily. This ginseng extract induced the phase 2 enzyme quinone reductase with an average concentration of doubling of enzyme activity of 190 microg/mL. Total ginsenoside content was 8.5 +/- 0.5%. Pharmacokinetic profiles of zidovudine and oxidative stress marker concentrations were measured post-zidovudine dose. American ginseng does not significantly affect the formation clearance of zidovudine to its glucuronide (ratio post- to pre-American ginseng = 1.17; 90% confidence interval: 0.95-1.45; P = .21), total clearance (ratio = 0.97; 0.82-1.14; P = .70), or plasma zidovudine AUC0-8 (ratio = 1.03; 0.87-1.21; P = .77). Oxidative stress biomarkers are reduced post-American ginseng (F2-isoprostane ratio = 0.79; 0.72-0.86; P < .001; 8-hydroxy-deoxyguanosine ratio = 0.74; 0.59-0.92; P = .02). Two weeks of American ginseng does not alter zidovudine pharmacokinetics but reduces oxidative stress markers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anti-HIV Agents; Antioxidants; Area Under Curve; Biomarkers, Pharmacological; Cells, Cultured; Chromatography, High Pressure Liquid; Deoxyguanosine; Dose-Response Relationship, Drug; Drug Interactions; F2-Isoprostanes; Female; Ginsenosides; HIV Infections; HIV Protease Inhibitors; Humans; Male; Metabolic Clearance Rate; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Panax; Phytotherapy; Plant Extracts; Zidovudine

Cross-sectional relationships were examined between regional brain volumes and mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells (PBMCs) of 47 HIV patients [mean age 51years; 81% with HIV RNA ≤50copies/mL] on combination antiretroviral therapy. The gene-specific DNA damage and repair assay measured mtDNA 8-oxo-dG break frequency. Magnetic resonance imaging was performed at 3T. Higher mtDNA 8-oxo-dG was associated with lateral ventricular enlargement and with decreased volumes of hippocampus, pallidum, and total subcortical gray matter, suggesting the involvement of systemic mitochondrial-specific oxidative stress in chronic HIV-related structural brain changes and cognitive difficulties. Clarification of the mechanism may provide potential therapeutic targets.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Atrophy; Cross-Sectional Studies; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Female; Gray Matter; Hippocampus; HIV Infections; Humans; Leukocytes, Mononuclear; Magnetic Resonance Imaging; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species

Oxidative stress has been implicated to contribute to HIV-induced kidney cell injury; however, the role of p53, a modulator of oxidative stress, has not been evaluated in the development of HIV-associated nephropathy (HIVAN). We hypothesized that mammalian target of rapamycin (mTOR) may be critical for the induction of p53-mediated oxidative kidney cell injury in HIVAN. To test our hypothesis, we evaluated the effect of an mTOR inhibitor, rapamycin, on kidney cell p53 expression, downstream signaling, and kidney cell injury in both in vivo and in vitro studies. Inhibition of the mTOR pathway resulted in downregulation of renal tissue p53 expression, associated downstream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, and apoptosed and 8-hydroxy deoxyguanosine (8-OHdG)-positive (+ve) cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated the redox-sensitive stress response program in the form of enhanced expression of manganese superoxide dismutase (MnSOD) and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition downregulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed a lack of expression of p53 as well as attenuated podocyte apoptosis, this suggests that mTOR is critical for kidney cell p53 activation and associated oxidative kidney cell injury in the HIV milieu.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; AIDS-Associated Nephropathy; Animals; Apoptosis; Catalase; Deoxyguanosine; Gene Silencing; HIV Infections; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Transgenic; Oxidative Stress; Podocytes; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Superoxide Dismutase; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir.. Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra(R)) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma.. There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased.. The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Body Fat Distribution; CD4 Lymphocyte Count; Deoxyguanosine; F2-Isoprostanes; Glutathione; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Lamivudine; Lopinavir; Male; Mitochondria; Organophosphonates; Pyrimidinones; Ritonavir; Stavudine; Tenofovir; Treatment Outcome; Viral Load

Mitochondrial toxicity of nucleoside analogues has been proposed to be the etiology of a range of side-effects from antiretroviral therapy of HIV infection. In this study, urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a metabolite of oxidized DNA, was measured to determine if antiretroviral therapy leads to oxidative damage to DNA. A cross-sectional study was carried out measuring urinary 8OH2'dG in three groups of HIV-infected patients: (1) antiretroviral medication naïve, (2) patients on antiretroviral medications without lipodystrophy and (3) patients on antiretroviral medications with lipodystrophy. Twenty-five patients were enrolled in each group. The mean spot urinary 8OH2'dG measurements per mg creatinine for the three groups were: antiretroviral naïve 4.27 +/- 0.61 (ng 8OH2'dG/mg creatinine +/- SEM), on antiretroviral medications without lipodystrophy 2.88 +/- 0.26, and on antiretroviral medications with lipodystrophy 3.27 +/- 0.30. The differences between the means of the three groups is not statistically significant (p = 0.055), and these results are not significantly different from reported values for healthy controls [A carbon column-based liquid chromatography electrochemical approach to routine 8-hydroxy-2-deoxyguanosine measurements in urine and other biologic matrices: a one-year evaluation of methods. Free Radical Biology and Medicine 27 (1999) 647-666].

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antiretroviral Therapy, Highly Active; Body Constitution; Case-Control Studies; Cross-Sectional Studies; Deoxyguanosine; DNA Damage; Female; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Male; Oxidative Stress