Quinones and Quinone Enzymes Part B

01.pdf......Page 6
02.pdf......Page 1
03.pdf......Page 2
Introduction......Page 8
NADH-CoQ Reductase......Page 9
Determination of NADH Dehydrogenase by Using Water-Soluble Electron Acceptors......Page 14
Metabolic Flux Control......Page 15
Proton Translocation......Page 18
Production of Superoxide Radical......Page 21
The Q-Cycle and Its Bypass Reactions......Page 26
Bypass Reaction 4......Page 29
Estimates of cyt bc1 and b6f Concentrations......Page 30
Measurements of the Bifurcated Oxidation of QH2......Page 31
Measurements of H+/e- Stoichiometries......Page 32
Inhibitor-Insensitive cyt c Reduction......Page 33
Measuring the Q Cycle Bypass Reactions via Superoxide or H2O2 Formation......Page 35
Probing the Involvement of ISP Domain Movements in Restricting Bypass Reactions......Page 38
Mylar Orientation of Cytochrome bc1/b6f Complexes......Page 39
Interpreting Oriented EPR Spectra......Page 41
Effects of Orientation of the EPR Transitions......Page 42
Conformational Heterogeneity......Page 43
Mosaic Spread......Page 44
A Simple Method for Estimating Changes in the Orientation and Ordering of Membrane-Bound Anisotropic EPR Signals......Page 45
Orientation of the g-Factor Axis With the Molecular Axis......Page 48
Acknowledgments......Page 50
Introduction......Page 51
Synthetic Strategies......Page 54
Analytical Procedures......Page 57
Incorporation of Radioactive and Stable Isotopes into Mitochondria-Targeted Coenzyme Q Derivatives......Page 60
Modifying and Measuring Coenzyme Q Redox State......Page 61
General Considerations......Page 63
Analysis of Mitochondrial Uptake of MitoQ......Page 65
Location of Targeted Coenzyme Q Derivatives Within Mitochondria......Page 69
Conclusion......Page 72
Acknowledgments......Page 73
Introduction......Page 74
Endotoxemic Animals......Page 77
Measurement of NOS Expression and Activity......Page 78
iNOS is Translocated to Mitochondria......Page 79
Ubiquinone Content and NO-Induced Hydrogen Peroxide Production by Mitochondria......Page 81
Mitochondrial Hydrogen Peroxide Production......Page 84
Detection of ONOO- in Mitochondria......Page 85
Acknowledgments......Page 88
Introduction......Page 89
Respiratory Chain and Ubiquinone......Page 90
Clinical Presentation of Coenzyme Q10 Depletion......Page 92
Detecting CoQ10 Deficiency......Page 94
Supplementation Therapy......Page 95
Conclusion......Page 96
Introduction......Page 97
Cytoprotective Activities of CoQ: Antioxidant Activity......Page 98
Cytoprotective Activities of CoQ: Protection Against Reductive Stress Caused by Complex I Inhibition in Isolated Rat Hepatocyte......Page 102
Cytoprotective Activities of CoQ: Re-establishing Mitochondrial Function in Complex I Inhibited Isolated Rat Hepatocytes......Page 103
Animals......Page 105
Measuring the Cytoprotective Effect of CoQ Analogs on Complex I Inhibited Hepatocytes......Page 106
Assaying the Cellular Reduction of CoQ1......Page 107
Ease of Reduction of CoQ Analogs......Page 108
Discussion......Page 110
Acknowledgments......Page 112
Introduction......Page 113
Absorption, Tissue Distribution, and Metabolism of Coenzyme Q10......Page 114
Effect of Dietary Coenzyme Q10 on Levels of Coenzyme Q10 in Tissues and Mitochondria......Page 115
Dietary Vitamin E and Coenzyme Q10 Uptake and Retention......Page 117
Isolation of Mitochondria......Page 118
Measurement of Coenzyme Q......Page 119
Implications of the Effect of Dietary Coenzyme Q10 and Vitamin E on Mitochondrial Coenzyme Q10......Page 120
Introduction......Page 121
Early Work on Mitochondrial Electron Transport and Vitamin K Metabolism......Page 122
Detoxification of Quinones via Two Electron Reduction......Page 123
Sharpening the Double-Edged Sword: NQO1 in Bioactivation......Page 124
NQO1 as a Component of a Stress Response: Stabilization of p53......Page 125
Pharmacogenetics of NQO1......Page 127
NQO1*2 Polymorphism......Page 128
NQO1*3 Polymorphism: Phenotype and Implications for NQO1 mRNA Alternative Splicing......Page 132
Acknowledgments......Page 150
Introduction......Page 151
Structure Description......Page 152
Monomer Structure......Page 155
Catalytic Site......Page 156
FAD Binding Site......Page 157
Electron Donor Binding......Page 159
Substrate Acceptor Binding......Page 161
Mechanism......Page 162
Structure-Based Mutagenesis......Page 165
Species Differences......Page 168
Crystallography Studies of Complexes of hNQO1 with Chemotherapeutic Compounds......Page 171
Good Substrates......Page 172
Poor Substrates and Inhibitors......Page 174
Summary......Page 176
CB1954......Page 179
Inhibitors......Page 180
Acknowledgments......Page 181
Introduction......Page 182
History......Page 183
pKs......Page 185
The Reductions......Page 187
The Enzymes......Page 190
DNA Interactions......Page 193
Other Targets for Diaziridinylbenzoquinones......Page 197
The Future......Page 201
Introduction......Page 202
Prodrugs: An Introduction......Page 203
CB 1954 (5-[Aziridin-1-yl]-2,4-Dinitrobenzamide)......Page 205
NAD(P)H Quinone Oxidoreductase 2 (NQO2)......Page 219
The Physiological Role of NQO2......Page 221
Functional Characterization of Truncated NQO1 and NQO1/NQO2 Chimeric Enzyme Preparations......Page 222
Bioactivation of CB 1954 by NQO2......Page 223
Biodistribution of NQO2 in Humans......Page 226
Conclusions......Page 228
Introduction......Page 230
MC as a Prototypic Bioreductive Agent......Page 231
Mechanism of the Reductive Activation of MC......Page 233
MC Bioreduction......Page 236
MC Resistance Protein A (MCRA)......Page 237
Mammalian MCRA Functional Homolog......Page 238
Search for Oxygen-Sensitive Resistance Mechanisms......Page 239
Methodology for the Indirect Determination of MC Activation......Page 242
Introduction......Page 243
Cell Cultures......Page 245
Preparation of Cell Extracts From HeLa Cells for Determination of NQO1 Activity......Page 246
Assay of NQO1 Activity in Cytosolic Fractions From HeLa Cells......Page 247
Role of Hydrogen Peroxide on Cell Density-Mediated Increase in NQO1 Activity......Page 248
Conclusions......Page 249
Acknowledgments......Page 252
Introduction......Page 253
Prochaska Bioassay Protocol......Page 255
Technical Improvements of the Assay......Page 257
Novel Findings Made with The Prochaska Bioassay......Page 258
Test Compound Matrix......Page 261
Dosing......Page 263
Bioassay Variability......Page 267
Acknowledgments......Page 268
Introduction......Page 269
Outer-Sphere Electron Transfer Model in Single-Electron Reduction of Quinones......Page 270
Structure-Activity Relationships in Single-Electron Reduction of Quinones by NADPH:Cytochrome P-450 Reductase and Ferredoxi......Page 271
Mechanisms of Two-Electron (Hydride) Transfer......Page 277
Structure-Activity Relationship in Reactions of Rat Liver NQO1......Page 283
Structure-Activity Relationship in Reactions of Enterobacter cloacae Nitroreductase......Page 286
Acknowledgments......Page 288
The Tumor Suppressor p53, Oxidoreductases and NAD......Page 289
NAD(P)H Quinone Oxidoreductase 1 (NQO1)......Page 294
Regulation of p53 Stability and p53-Dependent Apoptosis by NQO1......Page 296
Principle of p53-Dependent Apoptosis Assays......Page 300
Cells and Cell Culture......Page 301
Detection of Apoptotic Cell Death by Light Microscopy......Page 302
Detection of Apoptotic Cell Death by FACS Analysis......Page 303
Immunoblot Analysis......Page 304
Evolution of Fundamental Concepts And Principles of Chemical Carcinogenesis......Page 305
Mechanism of Tumor Initiation by PAHs......Page 306
Catechol Quinones as Mutagens Initiating Cancer And Other Diseases......Page 314
Formation of Estrogen Metabolites, Conjugates and DNA Adducts......Page 315
Imbalance in Estrogen Homeostasis......Page 317
Stable and Depurinating Catechol Estrogen-DNA Adducts......Page 321
Error-Prone Repair as an Initiating Mechanism of Breast Cancer......Page 325
Unifying Mechanism of Initiation of Cancer by Endogenous and Synthetic Estrogens......Page 327
Unifying Mechanism of Initiation of Cancer and Other Diseases by Catechol Quinones......Page 328
Acknowledgments......Page 331
Structure of NQO1......Page 332
Mechanism of Action of NQO1......Page 334
NQO1 Polymorphisms......Page 335
Expression of NQO1......Page 336
Induction of NQO1......Page 337
Induction of NQO1 in Normal and Cancer Cells......Page 338
NQO1 and Cancer Chemoprevention......Page 339
NQO1 and Cancer Chemotherapy......Page 342
Methods......Page 344
Induction of NQO1 in Mouse Cancer Cells and Effect on Antitumor Activity......Page 345
Induction of NQO1 in Human Cancer Cells and Effect on Antitumor Activity......Page 348
Induction of NQO1 in Cancer Cells and Enhancement of Antitumor Activity In Vivo......Page 356
Difficulties Related to Induction of NQO1 as a Method for Enhancing Antitumor Activity......Page 358
Future Perspectives......Page 361
Acknowledgments......Page 363
Introduction......Page 364
Elucidation of the Physiological Functions of NQO1......Page 365
Direct Demonstration That NQO1 Quenches Quinone-Dependent Generation of Reactive Oxygen Species......Page 367
Effects of Induction, Overexpression, and Inhibition of NQO1 on the Tolerance to Electrophile and Oxidative Toxicity......Page 368
Induction of NQO1 as Guide to Isolation, Identification, and Structure-Activity Analysis of Anticarcinogens......Page 369
Regulation of NQO1 by Antioxidant Response Elements (ARE) and Consequences of Disruption of the NQO1 Gene......Page 370
Epidemiological Links of NQO1 Polymorphism to the Risk of Developing Cancer......Page 371
Conclusions......Page 372
Activation and Detoxification of Naphthoquinones by NAD(P)H: Quinone Oxidoreductase......Page 374
Rates of Reduction of Naphthoquinones by QR......Page 376
Rates of Autoxidation of Hydroquinones......Page 377
Inhibition of Hydroquinone Autoxidation by QR......Page 378
Redox Cycling of Naphthoquinones in the Presence of QR......Page 379
Mechanism of Naphthohydroquinone Autoxidation......Page 380
Naphthoquinones That Form Hydroquinones That Cannot Be Stabilized by QR......Page 382
Menadione......Page 383
2-Hydroxy- and 5-Hydroxy-1,4-Naphthoquinone......Page 384
5-Amino-6-(7-Amino-5,8-Dihydro-6-Methoxy-5,8-Dioxo-2-Quinolinyl)-4-(2-Hydroxy-3,4-Dimethoxyphenyl)-3-Methyl-2-Pyridine Carbox......Page 385
Toxicity of Naphthoquinones In Vivo......Page 386
2-Amino-1,4-Naphthoquinone......Page 388
Conclusion......Page 389
Introduction......Page 391
Role of Phase II Enzymes in Cancer......Page 393
Quinone Reductase Induction and Cancer Chemoprevention......Page 394
Materials......Page 395
Assay Procedure......Page 396
Data Analysis......Page 397
Screening of Medicinal Plants......Page 398
Quinone Reductase Inducers Present in Edible Plants......Page 405
Isothiocyanates......Page 413
Steroids......Page 415
Flavonoids......Page 416
Chalcones......Page 420
Diarylheptanoid......Page 421
Miscellaneous Compounds......Page 422
Conclusions......Page 424
Acknowledgments......Page 425
Introduction......Page 426
NQO1 Enzyme Activity Following Oltipraz Treatment In Wild-Type and nrf2-Knockout Mice......Page 428
NQO1 mRNA Levels Following Oltipraz Treatment in Wild-Type and nrf2-Knockout Mice......Page 429
Susceptibility to Benzo[a]pyrene-Induced Gastric Tumor Formation in Wild-Type and nrf2-Deficient Mice......Page 430
Hepatic Gene Expression Patterns Following D3T Treatment in Wild-Type and nrf2-Disrupted Mice......Page 432
Cytotoxicity by Menadione in MEF Cells......Page 434
Introduction......Page 436
Inducer Potency of Phenolic Antioxidants Depends on Oxidative Lability......Page 438
Michael Reaction Acceptors as Inducers......Page 439
Class 1: Diphenols, Phenylenediamines, and Quinones......Page 441
Class 2: Michael Reaction Acceptors......Page 448
Class 3: Isothiocyanates, Dithiocarbamates, and Related Sulfur Compounds......Page 449
Class 4: 1,2-Dithiole-3-thiones, Oxathiolene Oxides, and Other Organosulfur Compounds......Page 450
Class 6: Trivalent Arsenicals......Page 455
Class 7: Heavy Metals......Page 457
Class 9: Carotenoids and Related Polyenes......Page 458
Implications of the Chemical Structures of Inducers for their Mechanism of Action......Page 460
Introduction......Page 462
Materials and Assay Methods......Page 463
Phase II Enzyme Induction by Allium-Derived Sulfides......Page 464
Relevance of Animal Studies to the Human Situation......Page 467
Conclusions......Page 469
Introduction......Page 470
Crucifers, Cancer Prevention and Quinone Reductase......Page 471
Sulforaphane......Page 472
Sulforaphane Nitrile......Page 474
Synergistic Effects of Glucosinolate Metabolites......Page 476
Genotype Variation in Glucosinolate Content of Cruciferous Vegetables......Page 478
Environmental Effects on Glucosinolate Content of Crucifers......Page 479
Microbial Conversion......Page 480
Effects of Processing on Quinone Reductase-Inducing Activity......Page 481
Effects of Vegetable Tissue Matrix on Bioavailability of Sulforaphane......Page 482
Effects in the Central Nervous System......Page 483
Mitochondrial Myopathies......Page 484
Pharmacokinetics of Orally Administered CoQ10......Page 486
The Antioxidant Properties and Effects of CoQ10 Supplementation in Animals......Page 487
Neuroprotective Effects in Animal Models of Neurodegeneration......Page 491
The Effects of CoQ10 Supplementation in Patients With Neurodegenerative Diseases......Page 493
Conclusions......Page 497
Introduction......Page 498
Neuronal Culture......Page 500
High-Performance Liquid Chromatography (HPLC-UV)......Page 501
Digital Fluorescence Microscopy and the Neuroprotective Potential of Coenzyme Q10......Page 502
Coenzyme Q9 and Coenzyme Q10......Page 503
Quantitative Estimation of Coenzyme Q9 and Q10......Page 506
Cell Transfection......Page 509
Discussion......Page 511
Repairing the Brain in Parkinson’s Disease and Providing Neuroprotection......Page 516
Summary and Conclusions......Page 518
Acknowledgments......Page 519
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