It is proposed that vascular endothelium has an intrinsic capacity to generate O2- for regulatory purposes such as inactivation of endothelium-derived relaxing factor. Ischaemia can disrupt the functioning of this oxidant-generating system. resulting in greater O2- generation when O2- is restored. Ischaemia-induced cellular injury can also lead to release of iron ions. that, upon reperfusion. cause conversion of O2- and H2O2 to powerfully-oxidizing species (such as. OH) that further injure the endothelium.
Conference Article| December 01 1978 Model Compounds with Superoxide Dismutase Activity: Iron Porphyrins and other Iron Complexes BARRY HALLIWELL; BARRY HALLIWELL 1Department of Biochemistry, University of London King's College, Strand, London WC2R 2LS, U.K. Search for other works by this author on: This Site PubMed Google Scholar ROBERT F. PASTERNACK ROBERT F. PASTERNACK 1Department of Biochemistry, University of London King's College, Strand, London WC2R 2LS, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1978) 6 (6): 1342–1343. https://doi.org/10.1042/bst0061342 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation BARRY HALLIWELL, ROBERT F. PASTERNACK; Model Compounds with Superoxide Dismutase Activity: Iron Porphyrins and other Iron Complexes. Biochem Soc Trans 1 December 1978; 6 (6): 1342–1343. doi: https://doi.org/10.1042/bst0061342 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1978 Biochemical Society1978 Article PDF first page preview Close Modal You do not currently have access to this content.
We previously showed that generation of reactive oxygen species during myocardial ischemia and reperfusion stimulates cardiac sympathetic afferent nerve endings. We hypothesized that, in this feline model of brief ischemia and reperfusion, HO. is produced during ischemia and the rate and concentration of production of HO.during reperfusion is dependent on the duration of myocardial ischemia. Therefore, we evaluated the time dependency of production of HO. during reperfusion after 2, 5, and 10 min of reversible occlusion of the left anterior descending (LAD) coronary artery to induce ischemia in cats (n = 10). Blood samples collected from the coronary vein at 0.25, 1, 2, and 4 min after 2 min of ischemia revealed net cumulative rate of production of p-, m-, and o-tyrosine of 99 +/- 31, 10 +/- 5.1, and 0.8 +/- 0.2 nmol.min-1.g-1, respectively. After 5 min of ischemia, net cumulative rates of production of p-, m-, and o-tyrosine during reperfusion were 177 +/- 63, 74 +/- 26, and 1.6 +/- 0.8 nmol.min-1.g-1, respectively, whereas after 10 min of ischemia production rates were 153 +/- 42, 78 +/- 29, and 2.1 +/- 0.5 nmol.min-1.g-1, respectively. The highest rate of production of tyrosines was observed immediately after ischemia, perhaps indicating a washout of HO.-derived products that had accumulated in the myocardium during ischemia. To evaluate production of HO. during ischemia, deoxygenated saline (PO2 10 +/- 0.9 mmHg) containing phenylalanine was perfused into the ischemic coronary vascular bed through a cannula placed in the LAD (n = 16). Perfusate was collected from the coronary vein during the 10 min of ischemia. Net production of HO. during ischemia, measured by the production of p-, m-, and o-tyrosine, was 82 +/- 11, 6.6 +/- 0.4, and 1.7 +/- 0.3 nmol.min-1.g-1, respectively. Pretreatment with deferoxamine (10 mg/kg, n = 7) or dimethylthiourea (10 mg/kg, n = 6) decreased net production of HO. during ischemia and reperfusion. These results demonstrate that HO. is produced during brief ischemia and reperfusion, with the greatest amount being produced immediately after ischemia. Additionally, we show that the duration of brief ischemia determines the rate of production of HO. during reperfusion.
Although silica has recently been designated as a carcinogen, its mechanism of carcinogenesis is not fully understood. Recent studies suggest that free‐radical reactions may play an important role in the initiation and progression of cancer. This article summarizes literature on the generation of reactive oxygen species (ROS) directly from silica and from silica‐stimulated cells. It also summarizes information concerning the role of ROS in silica‐induced DNA damage as well as in silica‐induced cell proliferation, including the effects of silica on the activation of nuclear transcription factors, induction of growth factors and oncogene expression, redox regulation of the p53 tumor suppressor gene, induction of apoptosis, and division of damaged cells. Understanding the role of ROS in silica‐mediated reactions may help develop therapeutic agents to block silica‐induced free radical reactions and thus prevent or attenuate silica‐induced carcinogenesis.
Bleomycin in the presence of iron(II) degrades DNA to form a thiobarbituric acid-reactive product. This has been made the basis of a specific assay method for ‘free’ iron in biological fluids. Human synovial fluid, human cerebrospinal fluid and rat pleural-exudate fluid were found to contain micromolar concentrations of ‘free’ iron, which would be sufficient to allow formation of the hydroxyl radical from superoxide and hydrogen peroxide generated in vivo. This assay method does not detect iron bound to transport proteins or to enzymes.
Vitamin C, a water-soluble glucose derivative, has considerable antioxidant activity in vitro, in part because of its ease of oxidation and because the semidehydroascorbate radical derived from it is of low reactivity. Vitamin C in vivo is an essential cofactor for a range of enzymes involved in diverse metabolic pathways, but much recent literature has focused on its antioxidant effects. Consumption of foods rich in Vitamin C (fruits and vegetables) is associated with decreased risk of cardiovascular disease, of many types of cancer and possibly of neurodegenerative disease, but the extent to which Vitamin C contributes to these effects is uncertain. Data using biomarkers of oxidative damage to DNA bases have given no compelling evidence to date that ascorbate supplements can decrease the levels of oxidative DNA damage in vivo, except perhaps in subjects with very low Vitamin C intakes. Similarly, there is no conclusive evidence from studies of strand breaks, micronuclei, or chromosomal aberrations for a protective effect of Vitamin C. There is limited evidence that supplements of Vitamin C might have beneficial effects in disorders of vascular function, and that diet-derived Vitamin C may decrease gastric cancer incidence in certain populations, but it is not clear whether it is the antioxidant or other properties of ascorbate that are responsible for these two actions.
Mesenteric ischemia reflexly activates the cardiovascular system. In addition, mesenteric ischemia and reperfusion generate reactive oxygen species. However, the ability of these short-lived reactive oxygen species to generate cardiovascular reflexes is unknown. We therefore investigated cardiovascular reflexes induced by serosal application of hydrogen peroxide (H2O2) to the gallbladder, stomach, or duodenum in anesthetized cats. Serosal application of hydrogen peroxide (44 mumols) to the gallbladder (n = 14) significantly (p less than 0.05) increased mean arterial blood pressure (MAP) by 37 +/- 6 mm Hg, left ventricular dP/dt by 1,893 +/- 416 mm Hg/sec, heart rate by 6 +/- 1 beats per minute, and systemic vascular resistance from 0.34 +/- 0.01 to 0.42 +/- 0.04 peripheral resistance units. The cardiovascular effects were dose-dependent over a range of 0.4 pmol to 132 mumols H2O2. Celiac and superior mesenteric ganglionectomy abolished H2O2-induced cardiovascular effects. Dimethylthiourea (10 mg/kg), a reactive oxygen species scavenger, significantly (p less than 0.05) attenuated 44 mumols H2O2-induced increases in MAP from 36 +/- 3 to 2 +/- 2 mm Hg. Deferoxamine (10 mg/kg) also significantly attenuated 44 mumols H2O2-induced increases in MAP from 40 +/- 7 to 19 +/- 10 mm Hg, but iron-loaded deferoxamine did not. Aspirin (50 mg/kg) did not attenuate H2O2-induced excitation of the cardiovascular system. These data suggest that H2O2 activates abdominal visceral afferents to reflexly stimulate the cardiovascular system by a mechanism involving hydroxyl radicals. Thus, reactive oxygen species could modulate systemic vascular tone by stimulating abdominal visceral afferents during mesenteric ischemia and reperfusion.
Desferrioxamine (deferoxamine) is an inhibitor of iron-dependent free radical reactions that has been used to investigate the role of such reactions in several animal model systems for human disease. In vitro, desferrioxamine is not only an iron chelator but also binds other metal ions, reacts with superoxide and hydroxyl radicals, affects eicosanoid synthesis, can act as a substrate for peroxidases and can generate a reactive nitroxide radical. However, considerations of desferrioxamine concentration in vivo suggest that its ability to inhibit iron-dependent free radical reactions is the major factor that accounts for desferrioxamine's generally-protective action in animal models of human disease.
