Molecular basis of oxidative stress chemistry mechanisms and disease pathogenesis

MOLECULAR BASIS OF OXIDATIVE STRESS MOLECULAR BASIS OF OXIDATIVE STRESS Chemistry, Mechanisms, and Disease Pathogenesis Edited by FREDERICK A VILLAMENA Department of Pharmacology and Davis Heart and Lung Institute The Ohio State University Columbus, Ohio Copyright © 2013 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com Requests to the Publisher for 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our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data Molecular basis of oxidative stress : chemistry, mechanisms, and disease pathogenesis / edited by Frederick A Villamena, Department of Pharmacology and Davis Heart and Lung Institute, The Ohio State University, Columbus, Ohio, USA pages cm Includes bibliographical references and index ISBN 978-0-470-57218-4 (cloth) Oxidative stress Oxidation I Villamena, Frederick A QD281.O9M65 2013 571.9'453–dc23 2013002853 Printed in the United States of America 10 CONTENTS Preface xvii About the Contributors xix Contributors xxv Chemistry of Reactive Species Frederick A Villamena 1.1 1.2 1.3 Redox Chemistry, Classification of Reactive Species, 1.2.1 Type of Orbitals, 1.2.2 Stability of Radicals, 1.2.3 ROS, 1.2.3.1 Oxygen Molecule (O2, Triplet Oxygen, Dioxygen), 1.2.3.2 Superoxide Radical Anion (O2•−), 1.2.3.3 Hydroperoxyl Radical (HO2•), 1.2.3.4 Hydrogen Peroxide (H2O2), 10 1.2.3.5 Hydroxyl Radical (HO•), 11 1.2.3.6 Singlet Oxygen (1O21Δg or 1O2*), 13 1.2.4 Reactive Nitrogen Species, 14 1.2.4.1 Nitric Oxide (NO or •NO), 14 1.2.4.2 Nitrogen Dioxide (•NO2), 16 1.2.4.3 Peroxynitrite (ONOO−), 17 1.2.5 Reactive Sulfur and Chlorine Species, 18 1.2.5.1 Thiyl or Sulfhydryl Radical (RS•), 18 1.2.5.2 Disulfide (RSSR), 19 1.2.5.3 Hypochlorous Acid (HOCl), 20 Reactivity, 22 1.3.1 Thermodynamic Considerations, 22 1.3.2 Kinetic Considerations, 24 1.3.2.1 Unimolecular or First-Order Reactions, 25 1.3.2.2 Bimolecular or Second-Order Reactions, 25 1.3.2.3 Transition State Theory, Reaction Coordinates and Activation Energies, 26 v vi CONTENTS 1.4 Origins of Reactive Species, 26 1.4.1 Biological Sources, 26 1.4.1.1 NADPH Oxidase, 26 1.4.1.2 Xanthine Oxidoreductase or Oxidase, 27 1.4.1.3 Mitochondrial Electron Transport Chain (METC), 27 1.4.1.4 Hemoglobin (Hb), 28 1.4.1.5 Nitric Oxide Synthases, 28 1.4.1.6 Cytochrome P450 (CYP), 29 1.4.1.7 Cyclooxygenase (COX) and Lipoxygenase (LPO), 29 1.4.1.8 Endoplasmic Reticulum (ER), 29 1.4.2 Nonbiochemical Sources, 29 1.4.2.1 Photolysis, 29 1.4.2.2 Sonochemical, 30 1.4.2.3 Photochemical, 30 1.4.2.4 Electrochemical, 30 1.4.2.5 Chemical, 30 1.5 Methods of Detection, 31 1.5.1 In Vitro, 32 1.5.1.1 Flourescence and Chemiluminescence, 32 1.5.1.2 UV-Vis Spectrophotometry and HPLC, 33 1.5.1.3 Immunochemical, 34 1.5.1.4 Electron Paramagnetic Resonance (EPR) Spectroscopy, 34 1.5.2 In Vivo, 38 1.5.2.1 Histochemical, 38 1.5.2.2 Immunocytochemical Methods, 38 1.5.2.3 Low Frequency EPR Imaging, 38 1.5.2.4 In Vivo EPR Spin Tapping-Ex Vivo Measurement, 38 References, 38 Lipid Peroxidation and Nitration Sean S Davies and Lilu Guo Overview, 49 2.1 Peroxidation of PUFAs, 49 2.1.1 Hydroperoxy Fatty Acid Isomers (HpETEs and HpODEs), 50 2.1.2 Hydroxy Fatty Acids (HETEs and HODEs), 51 2.1.3 Isoleukotrienes, 51 2.1.4 Epoxy Alcohols, 52 2.2 Cyclic Endoperoxides and Their Products, 52 2.2.1 Isoprostanes, 52 2.2.1.1 Isoprostane Regio- and Stereoisomers, 54 2.2.1.2 F2-Isoprostanes, 54 2.2.1.3 Other Major Isoprostane Products, 54 2.2.1.4 Minor Isoprostane Products, 56 2.2.2 Diepoxide Pathway Products, 57 2.2.2.1 Isofurans and Related Compounds, 57 2.2.3 Serial Cyclic Endoperoxides, 57 2.3 Fragmented Products of Lipid Peroxidation, 58 2.3.1 Short-Chain Alkanes, Aldehydes, and Acids, 58 2.3.2 Oxidatively Fragmented Phospholipids, 58 2.3.3 PAF Acetylhydrolase, 59 2.3.4 Hydroxyalkenals, 59 49 CONTENTS 2.3.5 Malondialdehyde, 61 2.3.6 Acrolein, 61 2.4 Epoxy Fatty Acids, 62 2.5 Lipid Nitrosylation, 62 2.5.1 Formation of Reactive Nitrogen Species, 63 2.5.2 Lipid Nitration Reactions, 63 2.5.3 Detection of Lipid Nitration In Vivo, 64 2.5.4 Bioactivities of Nitrated Lipids, 64 Summary, 65 References, 65 Protein Posttranslational Modification James L Hougland, Joseph Darling, and Susan Flynn 71 Overview, 71 3.1 Oxidative Stress-Related PTMs: Oxidation Reactions, 71 3.1.1 Cysteine, 71 3.1.1.1 Formation of Sulfur–Oxygen Adducts: Sulfenic, Sulfinic, and Sulfonic Acids, 72 3.1.1.2 Formation of Sulfur–Nitrogen Adducts: S-Nitrosothiols and Sulfonamides, 73 3.1.1.3 Formation of Sulfur–Sulfur Adducts: Disulfides and S-Glutathionylation, 74 3.1.1.4 Redoxins: Enzymes Catalyzing Cysteine Reduction, 75 3.1.2 Methionine, 76 3.1.3 Oxidation of Aromatic Amino Acids, 78 3.1.3.1 Tyrosine, 78 3.1.3.2 Tryptophan, 79 3.1.3.3 Histidine, 79 3.1.3.4 Phenylalanine, 79 3.1.4 Oxidation of Aliphatic Amino Acids, 79 3.2 Amino Acid Modification by Oxidation-Produced Electrophiles, 80 3.2.1 Electrophiles Formed by Oxidative Stress, 80 3.2.2 Carbonylation Reactions with Amino Acids, 80 3.3 Detection of Oxidative-Stress Related PTMs, 81 3.3.1 Mass Spectrometry, 81 3.3.2 Chemoselective Functionalization, 82 3.3.3 Cysteine Modifications, 82 3.3.3.1 Sulfenic Acids, 82 3.3.3.2 Cysteine-Nitrosothiols, 82 3.3.3.3 Cysteine-Glutathionylation, 82 3.3.4 Protein Carbonylation, 83 3.4 Role of PTMs in Cellular Redox Signaling, 84 Summary, 85 References, 85 DNA Oxidation Dessalegn B Nemera, Amy R Jones, and Edward J Merino Overview, 93 4.1 The Context of Cellular DNA Oxidation, 93 4.2 Oxidation of Oligonucleotides, 94 4.3 Examination of Specific Oxidative Lesions, 96 4.3.1 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine, 96 93 vii viii CONTENTS 4.3.2 Lesions on Ribose Bases Including Apurinic or Apyrimidinic Sites, 99 4.3.3 Novel Types of Ribose and Guanine Oxidative Lesions and Future Outlook, 101 4.3.3.1 Tandem Lesions, 101 4.3.3.2 Hyperoxidized Guanine, 102 4.3.3.3 Oxidative Cross-Links, 103 Future Outlook of DNA Oxidative Lesions, 103 References, 103 Downregulation of Antioxidants and Phase Proteins Hong Zhu, Jianmin Wang, Arben Santo, and Yunbo Li 113 Overview, 113 5.1 Definitions of Antioxidants and Phase Proteins, 113 5.1.1 Antioxidants, 113 5.1.2 Phase Proteins, 113 5.2 Roles in Oxidative Stress, 114 5.2.1 Superoxide Dismutase, 114 5.2.2 Catalase, 114 5.2.3 GSH and GSH-Related Enzymes, 114 5.2.3.1 GSH, 114 5.2.3.2 Glutathione Peroxidase, 115 5.2.3.3 Glutathione Reductase, 115 5.2.3.4 GST, 115 5.2.4 NAD(P)H:Quinone Oxidoreductase, 116 5.2.5 Heme Oxygenase, 116 5.2.6 Ferritin, 116 5.2.7 UDP-Glucuronosyltransferase, 116 5.3 Molecular Regulation, 116 5.3.1 General Consideration, 116 5.3.2 Nrf2 Signaling, 116 5.3.3 Other Regulators, 117 5.4 Induction in Chemoprevention, 117 5.4.1 Chemical Inducers, 117 5.4.2 Chemoprotection, 117 5.5 Downregulation, 117 5.5.1 Selective Chemical Inhibitors, 117 5.5.1.1 N,N-Diethyldithiocarbamate, 118 5.5.1.2 3-Amino-1,2,4-Triazole, 118 5.5.1.3 BSO, 118 5.5.1.4 Sulfasalazine, 118 5.5.1.5 Dicumarol, 118 5.5.2 Drugs and Environmental Toxic Agents, 118 Conclusions and Perspectives, 119 References, 119 Mitochondrial Dysfunction Yeong-Renn Chen Overview, 123 6.1 Mitochondria and Submitochondrial Particles, 123 6.2 Energy Transduction, 125 6.3 Mitochondrial Stress, 125 123 CONTENTS 6.4 Superoxide Radical Anion Generation as Mediated by ETC and Disease Pathogenesis, 126 6.4.1 Mediation of O2•− Generation by Complex I, 126 6.4.1.1 The Role of FMN Moiety, 126 6.4.1.2 The Role of Ubiquinone-Binding Domain, 126 6.4.1.3 The Role of Iron–Sulfur Clusters, 127 6.4.1.4 The Role of Cysteinyl Redox Domains, 127 6.4.1.5 Complex I, Free Radicals, and Parkinsonism, 129 6.4.2 Mediation of O2•− Generation by Complex II, 129 6.4.2.1 The Role of FAD Moiety, 129 6.4.2.2 The Role of Ubiquinone-Binding Site, 129 6.4.2.3 Mutations of Complex II Are Related with Mitochondrial Diseases, 129 6.4.2.4 Mitochondrial Complex II in Myocardial Infarction, 130 6.4.3 Mediation of O2•− Generation by Complex III, 130 6.4.3.1 The Q-Cycle Mediated by Complex III, 130 6.4.3.2 Role of Q Cycle in O2•− Generation, 131 6.4.3.3 The Role of Cytochrome bL in O2•− Generation, 132 6.4.3.4 Bidirectionality of Superoxide Release as Mediated by Complex III, 132 6.4.4 Complex IV, 132 Summary, 133 References, 134 NADPH Oxidases: Structure and Function Mark T Quinn Overview, 137 7.1 Introduction, 137 7.2 Phagocyte NADPH Oxidase Structure, 137 7.2.1 Flavocytochrome b, 138 7.2.2 p47phox, 139 7.2.3 p67phox, 140 7.2.4 p40 phox, 141 7.2.5 Rac1/2, 141 7.2.6 Rap1A, 142 7.3 Phagocyte ROS Production, 142 7.3.1 Superoxide Anion (O2•−), 142 7.3.2 Hydrogen Peroxide (H2O2), 143 7.3.3 Hypochlorous Acid (HOCl), 143 7.3.4 Hydroxyl Radical (HO•), 143 7.3.5 Singlet Oxygen (1O2*), 144 7.3.6 Nitric Oxide (•NO) and Peroxynitrite (OONO−), 144 7.4 Phagocyte NADPH Oxidase Function, 145 7.5 Nonphagocyte NADPH Oxidase Structure, 146 7.5.1 NOX1, 147 7.5.2 NOX3, 149 7.5.3 NOX4, 149 7.5.4 NOX5, 150 7.5.5 DUOX1 and DUOX2, 150 7.5.6 NOXO1, 150 7.5.7 NOXA1, 151 137 ix x CONTENTS 7.6 7.7 Nonphagocyte ROS Production, 151 Functions of Nonphagocyte NADPH Oxidases, 152 7.7.1 Cardiovascular System, 152 7.7.2 Renal System, 154 7.7.3 Pulmonary System, 155 7.7.4 Central Nervous System, 156 7.7.5 Gastrointestinal System, 157 7.7.6 Hepatic System, 158 7.7.7 Thyroid Gland, 159 Summary, 159 Acknowledgments, 159 References, 160 Cell Signaling and Transcription Imran Rehmani, Fange Liu, and Aimin Liu 179 Overview, 179 8.1 Common Mechanisms of Redox Signaling, 179 8.2 Redox and Oxygen-Sensitive Transcription Factors in Prokaryotes, 181 8.2.1 Fe–S Cluster Proteins, 181 8.2.2 Prokaryotic Hydrogen Peroxide Sensors: Proteins Utilizing Reactive Thiols, 182 8.2.3 PerR: A Unique Metalloprotein Sensor of Hydrogen Peroxide, 182 8.2.4 Summary, 184 8.3 Redox Signaling in Metazoans, 185 8.3.1 Primary Sources of ROS in Eukaryotic Redox Signaling, 185 8.3.2 The Floodgate Hypothesis, 186 8.3.3 Redox Regulation of Kinase and Phosphatase Activity, 187 8.3.4 Communication between ROS and Calcium Signaling, 188 8.3.5 Redox Modulation of Transcription Factors, 188 8.3.6 Summary, 189 8.4 Oxygen Sensing in Metazoans, 190 8.4.1 HIF, 190 8.4.2 PHD Enzymes, 190 8.4.3 FIH, 191 8.4.4 Factors Influencing Fe(II)/α-KG Dependent Enzymes, 192 8.4.5 ROS and Oxygen Sensing, 193 8.4.6 Summary, 193 8.5 Medical Significance of Redox and Oxygen-Sensing Pathways, 194 8.5.1 Cancer, 194 8.5.2 Vascular Pathophysiology, 194 Concluding Remarks, 195 References, 195 Oxidative Stress and Redox Signaling in Carcinogenesis Rodrigo Franco, Aracely Garcia-Garcia, Thomas B Kryston, Alexandros G Georgakilas, Mihalis I Panayiotidis, and Aglaia Pappa Overview, 203 9.1 Redox Environment and Cancer, 203 9.1.1 Pro-Oxidant Environment and Endogenous Sources of RS in Cancer, 203 9.1.1.1 Reactive Oxygen Species (ROS)-Generating NADPH Oxidases and Cancer, 203 203 396 SYNTHETIC ANTIOXIDANTS equal in the two groups, and no evidence of efficacy for any secondary end points, including scores on neurologic and activities of daily living scales, was observed A pooled analysis of the SAINT I and II trials further concluded that NXY-059 was not effective in the combined trials.215 Although both preclinical and clinical trials were supposed to be developed in accordance with the Stroke Therapy Academic Industry Roundtable (STAIR), the very disappointing outcome of the SAINT II trial led to the termination of NXY-059 as therapeutics for acute ischemic stroke Critiques on how the development of NXY-059 was conducted have been raised Savitz pointed out the need for more rigorous and strenuous testing at the preclinical stage.216 Among Savitz’s critiques about the preclinical studies, one can cite the lack of sufficient independent studies in different laboratories in order to confirm preliminary findings as well as the absence of information on NXY-059 mechanisms of action and whether it enters the brain parenchyma after embolic stroke Clinical trial also appeared to be inadequately designed because of inappropriate treatment windows and inclusion of diverse stroke patients 15.4.5 The Controversial Mode of Action of Nitrones Considering the very broad activity of nitrones as discussed above and reviewed by others, there had been controversy on the mechanism of action of nitrone in biological systems Since they were initially employed as probes for spin-trapping experiments, their biological activity had been first explained based on their radical trapping activity However, several experimental evidences have strongly put aside the trapping activity and other mechanisms have been suggested For instance, the rate of reaction of PBN with radical is quite slow,135 that is, 105–107 M−1.s−1 and therefore, during spin trapping experiments in chemical milieu, PBN must be present at high concentration (10–50 mM) to trap a significant fraction of free radicals These concentrations used are roughly 1000 times higher than those commonly employed in biological studies of protection (10–50 μM) Moreover, the concentration of nitrones in the target tissues is usually inferior at 0.5 mM, which is not sufficient to quench all the radical species As previously discussed above, in experimental stroke model, it had been observed that PBN led to protection even if administered up to hours after the start of reperfusion.198 Preclinical and clinical studies with PBN and NXY-059 confirmed without any doubt the ability of nitrones to prevent stroke induced-damages even when administered of few hours after the onset of stroke These findings further support the invalidation of the spin-trapping mechanism as the primary mode of action of nitrones Another demonstration by Floyd and Carney was provided with aging gerbils that were chronically administered with PBN for 14 days.217 Although the treatment ceased several days before the stroke, treated animals were more resistant than untreated ones Considering the half-life of PBN ∼2 hours, it is very likely that none of the nitrone is still present days after cessation of the treatment, thus demonstrating that the classical mass action of spin traps is not solely responsible for the pharmacological activities of nitrones 15.4.5.1 Antioxidant Property of PBN against Lipid Peroxydation Its very poor antioxidant activity have been observed in simple models of lipid peroxidation demonstrating that nitrones not act as classical chainbreaking antioxidants.218,219 While PBN inhibited lipid peroxidation at mM, antioxidants such as γ-tocopherol or BHT were a thousand-fold more efficient, exhibiting antioxidant protection at only μM.218 15.4.5.2 Anti-Inflammatory and Anti-Apopotic Properties of Nitrones There is strong evidence that PBN acts to quell signal transduction processes and therefore provides potent anti-inflammatory and antiapoptotic properties.161,162,164,191 PBN has been shown to inhibit the activity of cytokines and transcription factors such as NF-κB, which can rapidly activate the expression of genes involved in inflammation.220–222 The inhibition of the COX2 catalytic activity and the decrease of the steady state COX2 mRNA level was also demonstrated Other rationales for nitrone protection in animal models showing that PBN can inhibit gene induction of heat shock proteins include c-fos and inducible nitric oxide synthase as well One of the first and yet convincing study that illustrated the importance of neuro-inflammation in brain injury and the potency of PBN to preserve brain function by quelling exacerbated signal transduction processes is that by Floyd et al in 2000.223 Kainate administration to rats led to injury to the hippocampus providing a good experimental model of epilepsy Administration of PBN prevented apoptotic neuron loss and mortality, and immunohistochemical examination showed that the Kainate-induced activation of p38 MAP kinase and NF-κB was suppressed by PBN Since then, numerous reports have shown the ability of nitrone to suppress the proinflammatory cytokine and stressors mediated induction of genes in a wide range of biological systems In the review by Green et al are listed some important biochemical consequences of nitrone administration in vitro, ex vivo, and in vivo, which may be associated with neuroprotection (Table 15.2).204 NITRONES TABLE 15.2 et al.204) 397 Some Biochemical Consequences of PBN Administration In Vitro, In Vivo, and Ex Vivo (Adapted from Green In vitro In vivo or ex vivo 10 11 12 13 14 Inhibition of iNOS induction in HIV-1 envelope Potentiation of H2O2-induced Erk and Src kinase in human Stimulation of H2O2-induced activation of the prosurvival Erk signal transduction pathway Protection of primary cerebellar neurones from glutamate toxicity Facilitation of postischemic reperfusion following transient MCAO Inhibition of apoptosis-associated gene expression in endotoxin-treated rats Suppression of caspase-3 activation following global ischemia Prevention of the decrease in stimulated (+ADP), nonstimulated (–ADP) and uncoupled rats following transient MCAO Inhibition of endotoxin-induced induction of nitric oxide synthase Improvement of the rate of metabolic recovery, acidosis rebound, and ATP renewal in rat brain following transient focal ischemia Suppresion of c-fos expression in postischemic gerbil brain Attenuation of the secondary mitochondrial dysfunction after transient focal ischemia Reduction of the number of positive τ-oligodendrocytes after focal ischemia Prevention of cytotoxic ischemia following malonate 15.4.5.3 Action on Membrane Enzymes PBN was shown to act as a reversible calcium channel blocker at concentrations far lower than those required for free radical detection by EPR, and it was concluded that removal of free radicals may not contribute to the nitrone-induced vasorelaxation.224 The potency of PBN to inhibit acetylcholinesterase activity, an enzyme that converts acetylcholine into the inactive metabolites choline and acetate, with a Ki of 0.58 mM, was also reported.225 15.4.5.4 Interaction with the Mitochondrial Metabolism Hensley et al demonstrated that PBN interacts with the mitochondrial complex I, inhibiting complex-I stimulated H2O2 flux and nitro blue tetrazolium reduction.226 This site-specific interaction of PBN with mitochondrial flavin deshydrogenases, which leads to alteration of the electron transit within the enzymes, is believed to participate to the broad antioxidant and anti-inflammatory action of nitrones Interaction of PBN with mitochondrial complex I was also demonstrated in the prevention of the doxorubicin-induced apoptosis in bovine aortic endothelial cells.171 Indeed, it was shown that doxorubicin inactivated complex-I by a superoxide-dependant mechanism and that complex-I activity was restored by PBN, confirming the first observations by Hensley et al Pretreatment of cells with PBN also resulted in a full inhibition of DOX-induced cytochrome c release and a complete restoration of GSH levels Other mitochondrial-specific interactions of nitrones were next reported An increase of endogenous mitochondrial superoxide production, following intra- thecal injection of complex III inhibitor antimycin A, has been demonstrated to induce hyperalgesia in mice.227 PBN significantly reduced hyperalgesia 30 and 60 minutes following the treatment providing transient antinociception irrespective to the administration mode of PBN, that is, intraperitoneal or intrathecal Mitochondrial impairment has been associated with cardiac dysfunction in Chagas’ disease, a parasitic disease whose about 40% of seropositive patients develop cardiomyopathy In infected mice, oxidative stress and alteration of mitochondrial functions in the myocardium are observed as well as similar cardiac dysfunction to what is observed in human chagasic patients Treatment of infected mice with PBN prevented mitochondrial oxidative damage and significantly improved respiratory complex activities.228,229 The impairment of a specific site of complex III 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Acidosis, intracellular, 317 Acrolein, 58, 61–62 Actin, 74, 78 Activator protein 1, 346 Adderall, 256 Adenine, 96 Adenosine, 316, 321 Adenosine diphosphate (ADP), 27, 114, 123–125, 316, 318 Adenosine monophosphate (AMP), 27, 316, 318 cyclic, 243, 245, 352 Adenosine triphosphate (ATP), 27, 73, 114, 123–125, 130, 132, 190, 220, 238, 240–241, 316, 318–319, 352 synthase, 362–364, 397, Adenylation, 78 ADMA, see Asymmetric dimethylarginine Advanced lipidation end products (ALE), 80 Aflatoxin B1, 250 Aging, 237, 252 and DNA repair, 268–269 and METH, 262 Airway inflammation, 347 obstructions, 348 Alanine, 318 Alcohol dehydrogenase class III (ADH), 74 Aldehyde oxidase (AO), 314, 316, 318 Aldehydes in atherosclerosis, 329–335 in I-R, 314 Alkoxyl radical, 51–52, 58, 62 Allopurinol, 318, 320 See also Inhibitors Allysine, 79 Alzheimer’s disease, 80, 194, 238–241, 250, 253–254, 263, 266, 277–278, 360 Amadori rearrangements, 80 Amino acids, free, 318–319 Aminoglycoside, 351 2-amino-3-keto butyric acid, 80 3-amino-1,2,4-triazole, 117 Amphetamine(s), 252, 255–263 affinities to uptake transporters, 260 bioactivation by PHSs, 252–253 history, 255–256 metabolism by CYPs, 257–259 neurotoxicity, 261–263 pharmacokinetics, 256–257 SOD protection against toxicity, 266 uses, 255–256 AMPO, 390 See also Nitrones Amyotrophic lateral sclerosis (ALS), 239, 241, 253–4, 277–278, 360 Angiotensin II, 150, 152–156, 158 Antibiotics, 181 Antibody, 127–128 Antidepressants, 240 Antiinflammatory cytokines, 346 Antimicrobial, 346–350 Antioxidant response element (ARE), 269–270, 274–275 Antioxidants in cell signaling, 179, 180, 182, 185–186, 188, 190, 193–195 enzymes, 94, 114–116, 263–268, 312–313, 318, 321 synthetic, 377–398 Antipsychotics, 240 AP-1, see Activator protein Apical transporter, 348 Molecular Basis of Oxidative Stress: Chemistry, Mechanisms, and Disease Pathogenesis, First Edition Edited by Frederick A Villamena © 2013 John Wiley & Sons, Inc Published 2013 by John Wiley & Sons, Inc 407 408 INDEX Apolipoprotein A1 (apo A1), 334 B (apo B), 331 Apoptosis, 75, 216–219 Bcl-2, 218 Bcl-xl, 218 BH3-only proteins, 218 cytochrome c (Cyt c), 217–218 death receptors, 217–218 endoplasmic reticulum (ER) stress, 218–219 extrinsic pathway, see Death receptors glutathione, 217–219 in I-R, 313, 315, 319, 320 intrinsic pathway, see Mitochondrial pathway mitochondrial pathway, 218 multidrug-resistance proteins (MRP1), 220 from NADPH oxidases, 145, 146, 148, 155–156, 158 p53, 219 and PTM, 75 TNF-related apoptosis-inducing ligand (TRAIL), 217–218 Apurinic/apyrimidinic (AP) sites, 99, 100–101 Aquaporins, 351 Arachidonic acid (AA), 50–52, 54, 57–65, 240, 242, 246–249, 252 ARE, see Antioxidant response element Arsenic, 94–95 Ascorbic acid, 262, 268, 347 Asparaginyl hydroxylase factor inhibiting HIF (FIH), 191–192 Aspartate, 318 Astrocytes, 239–241, 250, 254, 263, 266–268, 276–279 Asymmetric dimethylarginine (ADMA), 318 Ataluren, 351 Ataxia telangiectasia mutated (ATM), 238–239, 268 Atherosclerosis, 329–333, 384 Attention deficit–hyperactivity disorder (ADHD), 256, 260 Autophagy, 219, 319–320 See also Cell death Azelaic acid (AZA), 334 Bacteria colonization, 346–347 BALF, see Broncho alveolar lavage fluid Benzo[a]pyrene-7,8-dihydrodiol, 250 Beta-amyloid (AB), 241, 250 β-carotene, 347 Beta-scission reactions formation of fragmented lipid products, 51–52, 58–62 role of iron and copper, 50–51, 58, 61–62 Biomarker for COPD, 349 for neurodegenerative disorders, 360 Biotin, 82 Blood–brain barrier (BBB), 263 and METH, 256 Brad 1, 189 Bradykinin, 321 Brain infarction, 385, 387 Breast cancer (Brca1), 238–239, 269 Broncho alveolar lavage fluid, 352 Bronchodilation, 349 Buthionine sulfoximine, 117–118 Calcification, 331 Calcium in cell signaling, 186–188 in dendritic spines, 250 in excitotoxicity, 241 homeostasis, 185, 188, 195 in mitochondria, 238 Calcium-dependent proteases, 241 Calicheamicin, 100 CAMP, see Adenosine monophosphate, cyclic Cancer, 203–235 apoptosis, 216–219 autophagy, 219 catalase, 206 cell signaling, 193–194 cycloxygenases, 205 DNA methylation, 216 DNA methyl-transferases (DMTs), 216 drug resistance, 219–220 epigenetics, 213, 216 glucose-6-phosphate dehydrogenase, 206 glutathione, 205–206, 208, 217 glutathione peroxidases (GPx), 206 glutathione-SNO (S-nitrosoglutathione or GSNO), 208 glutathione-S-transferases, 216, 220 protein glutathionylation, 208 γ -glutamylcysteine synthetase, 205 Carbohydrate oxidation biomarkers in neurodegenerative disorders, 366 Carcinogenesis, 203–235 See also Cancer Cardiac, 311–321 See also Heart ischemia, 311–314, 318 reperfusion, 311, 314, 318 transplantation, 321 Cardiolipin, 315 Cardiomyocyte(s), 311, 314–315, 318–320 Cardioplegic, arrest, 312, 318 buffer, 318 ischemia, 312 solution, 312 Cardiovascular disease (CVD), 330, 334–335 Catalase, 114, 143–146, 159, 238–239, 251–252, 377–378 in brain, 262, 267 in cancer, 206 in I-R, 313 and NADPH, 264 mimetics, 380 in neurodegenerative disease, 278 Celecoxib (Celebrex), 249, 254 Cell death, 311, 315, 319–321 apoptosis, 319–320 autophagy, 319–320 necrosis, 319–320 programmed, 315, 319 Cell signaling, 179, 180, 184–186, 193–194, 317–318 INDEX Cellular enzymes, 313 organelles, 312–313 thiolstat, 71, 84 CF, see cystic fibrosis CFTR, see Cystic fibrosis transmembrane regulator CGMP-dependent protein kinase (PKG)I-α, 85 Chemiluminescence, 32 Chemoprevention, 117 Chemoselective functionalization, 82 Chloride channel, 345, 348 conductance, 351–352 transport, 348 transporter, 348, 351 ChPBNL, 393 See also Nitrones Chromium, 94–95, 98 Chronic granulomatous disease (CGD), 138–141, 145–146, 154, infections, 346 lung infections, 345 obstructive pulmonary disease COPD, 80 Citric acid cycle, 180, 192 Clorgyline, 240 Cockayne syndrome B (CSB), 238–239, 269 Cofactors, 316 BH4, 315, 317–318, 320 Colon epithelial cells, 186 Complex I, 123, 125–129, 133, 312, 314, 316 Complex II, 126, 129, 130, 133 Complex III, 125–126, 129–133, 312, 315 Complex IV, 125–126, 132–133, 315 Conserved sequence block, 96 Copper-zinc superoxide dismutase (CuZnSOD, SOD1), see Superoxide dismutase Coronary artery disease, 311, 320 Coronary heart disease (CHD), 333 COX, see Cyclooxygenase CPI-1429, 393–394 See also Nitrones C-Rel, see Proto-oncogene cRel Cross-links, see Lesions Cu,Zn superoxide dismutase (CuZnSOD, SOD1), 79, 253, 313 in neurodegenerative diseases, 278 Cyanuric acid, 102 Cyclooxygenase-1 (COX-1), 242 See also PHS-1; prostaglandin H synthases Cyclooxygenase-1b (COX-1b) (COX-3), 244 Cyclooygenase, 29 See also COX-1; COX-2 Cyclooxygenase-2 (COX-2), 242 See also PHS-2; Prostaglandin H synthases CYP1A2, 258 See also Cytochromes P450 CYP2D6, 240, 257–259 See also Cytochromes P450 expression in brain, 259 CYP2E1, 240 See also Cytochromes P450 Cysteinyl redox domains, 127 Cystic fibrosis (CF), 80, 345 diagnostic tests for, 348 gene, 345 lung disease, 345–347, 351 Cystic fibrosis transmembrane regulator (CFTR) KO mice, 347–349, 352 mutations, 349, 351 potentiators, 352 Cytochrome bH or heme bH, 130–131 Cytochrome bL or heme bL, 130–133 Cytochrome c, 131–132 in I-R, 314–316, 318–319 See also Nitrate/Nitrite reductase Cytochromes P450 (CYPs), 240 metabolism of amphetamines, 257–259 Cytokine, 187, 193–194 and microglia, 241 and NOS, 240 as PHS activators, 245 Cytosolic phospholipase A2 (cPLA2), 240 Death receptors, 217, 219 Deoxymyoglobin, 316 See also Nitrate/Nitrite reductase 2-deoxypentos-4-ulose abasic site, 96 2′-deoxyribonolactone, 96,100 Deoxyribonucleic acid (DNA), 94–103 and histone proteins, 94 backbone reactivity, 96 damage, 349 See also Oxidative DNA damage duplex, kinetic changes to, 99 holes, 96 oxidation, 252–253 repair, 268–269 2′-deoxyribose (dR), 99–102 and hydrogen abstraction, 100 lesions, 101 oxidation, 100 radical, 100 DEPMPO, 390 See also Nitrones Detection of reactive species, 31–38 in vitro, 32 in vivo, 38 Dexedrine, 256 Diabetes, 194 Dicumarol, 118 Dihydroxyphenylacetic acid (DOPAC), 251–252, 255 Dilated cardiomyopathy, 313 Dimedone, 82 Dimethyl fumarate (DMF), 276–277, 279 Dioxetane, 52, 59, 61 1,2-dioxilane ring, 52 1,2-dioxolanylcarbinyl, 52, 57 Diradical, 190 Dismutation, see Superoxide radical Disulfide, 19, 180 formation, 19 with nucleophiles, 19 oxidation, 19 reaction with thiols, 19 reduction, 20 3,3′-dityrosine, 78 DJ-1, 269–270, 272, 277–278 409 410 INDEX DMPO, 36 as antioxidant, 389–394 DNA, see Deoxyribonucleic acid DNA-mediated charge transport, 96 Dopamine, 154, 156, 240, 251–252, 255, 259 and METH neurotoxicity, 261–262 quinones, 251, 254 Double strand breaks (DSBs), 100 DPI, 126–127 Drug resistance in cancer, 219 glutathione, 219 Dual oxidases, 347 See also DUOX, DUOX1, DUOX2 DUOX, 147–148, 150, 152, 155–159 DUOX1, 147–148, 150, 152, 155, 159 DUOX2, 147–148, 150, 152, 155, 157, 159 Ebselen, 382–384 anti-inflammatory effect of, 382, 384 BXT-51072, 385 BXT-51077, 385 clinical trial (ischemic stroke), 384 ebselen diselenide, 383–385 ebselen selenol, 383–384 ebselen Se-oxide, 384 glutathione peroxydase activity of, 382 inhibiting activity of lipoxygenases, 384 inhibition of iNOS by, 384 inhibition of lipid peroxidation by, 384 peroxynitrite scavenging by, 384 reaction with thiols, 383–384 reduction and scavenging properties of, 383 substrate for mammalian thioredoxin reductase, 384–385 synthesis of, 382 Edaravone (also radicut, MC-186) , 385–388 enhancement of eNOS expression, 385, 387 inhibition of iNOS, 385, 387 neuroprotective effect of, 387 pharmacokinetics of, 385 protection against amyotrophic lateral sclerosis (ALS), 387 protection against brain infraction, 385, 387 protection against noise-induced hearing loss, 388 protection against retinal degeneration, 387 reduction of myocardial injuries, 385–387 scavenging properties of, 385–386 Eicosanoids, 241–242 Elastase, 347 Electron leakage, 28, 312 Electron paramagnetic resonance (EPR) imaging, 38 oximetry, 38 spectroscopy, 34, 126–130, 317, 385–386, 389–390, 397 Electron transfer, Electron transport chain (ETC), see Mitochondrial electron transport chain (METC) Electronegative atoms, Electronegativity, Electrophile response element (EpRE), 269 See also Antioxidant response element Electrospray ionization ( ESI) mass spectrometry, 81 EMPO, 390 See also Nitrones Endonuclease III ( NTH), 102 Endoperoxides, 52–54, 57, 61–62 Endoplasmic reticulum (ER), 29, 312 stress, 313 Endothelial, 311, 315–316, 318–320 cell(s), 311, 316, 318–319 dysfunction, 320 Endothelial nitric oxide synthase (eNOS, NOS3), see Nitric oxide synthase Endothelin, 314, 321 Energy transduction, 125 ENOS/NOS3, see Nitric oxide synthase Epithelial lining fluid, 346, 349 See also ELF Epoxide hydrolase, 313 Epoxy alcohols and peroxyls , 51–53, 57 aldehydes, 61 fatty acids, 59, 62 isoprostanes, 57 Erythorose abasic site, 96 Excision repair cross complementing (ERCC1), 101 Excitotoxicity, 241, 253 source of ROS, 241 4-exo-cyclization, 52 5-exo-cyclization, 52, 55, 57 ΔF508 mutation, 345 FADH•− or FADH• semiquinone, 129 Fat soluble antioxidant vitamins, 347 Fe(IV)=O intermediate, see Iron-oxo intermediate Febuxostat, 320 See also Inhibitors 2Fe-2S, 3Fe-4S, 4Fe-4S, see Iron-sulfur cluster Fe-DETC, see Iron diethyldithiocarbamate Fe-MGD, see Iron methyldithiocarbamate Fenton-type reaction, 125, 183–184, 378, 382 Ferritin, 116, 347 FIH, see Asparaginyl hydroxylase factor inhibiting HIF Flavin adenine dinucleotide (FAD), 129–130, 138–140, 147, 149, 152, 186 Flavin mononucleotide (FMN), 126–128 Flavocytochrome b, 138 See also Flavocytochrome b558, gp91phox, NOX2 Flavocytochrome b558, 139 See also Flavocytochrome b, gp91phox, NOX2 Fluorescence, 32 Fluoroquinolone, 181 FMN, see Flavin mononucleotide FMNH•− or FMNH• semiquinone, 126 Forced vital capacity, 352 3-formyl phosphate, 96 Forskolin, 352 Fp subcomplex, 126–127 Fragmentation ... MOLECULAR BASIS OF OXIDATIVE STRESS Chemistry, Mechanisms, and Disease Pathogenesis Edited by FREDERICK A VILLAMENA Department of Pharmacology and Davis Heart and Lung Institute... Cataloging-in-Publication Data Molecular basis of oxidative stress : chemistry, mechanisms, and disease pathogenesis / edited by Frederick A Villamena, Department of Pharmacology and Davis Heart and Lung Institute,... encompasses the understanding of the mechanisms of oxidative stress and autophagy in experimental Parkinson’s disease models Alexandros G Georgakilas is an Associate Professor of Biology at East