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Volume 1
• Part 1 Basic Concepts 1
1 Contributions of Plasma Protein Binding and Membrane Transporters to Drug?]Induced Mitochondrial Toxicity 3
2 The Role of Transporters in Drug Accumulation and Mitochondrial Toxicity 15
3 Structure–Activity Modeling of Mitochondrial Dysfunction 25
4 Mitochondria?]Targeted Cytochromes P450 Modulate Adverse Drug Metabolism and Xenobiotic Induced Toxicity 35
• Part 2 Organ Drug Toxicity: Mitochondrial Etiology 47
5 Mitochondrial Dysfunction in Drug?]Induced Liver Injury 49
6 Evaluating Mitotoxicity as Either a Single or Multi?]Mechanistic Insult in the Context of Hepatotoxicity 73
7 Cardiotoxicity of Drugs: Role of Mitochondria 93
8 Skeletal Muscle Mitochondrial Toxicity 111
9 Manifestations of Drug Toxicity on Mitochondria in the Nervous System 133
10 Nephrotoxicity: Increasing Evidence for a Key Role of Mitochondrial Injury and Dysfunction and Therapeutic Implications 169
11 Mammalian Sperm Mitochondrial Function as Affected by Environmental Toxicants, Substances of Abuse, and Other Chemical Compounds 185
• Part 3 Methods to Detect Mitochondrial Toxicity: In Vitro, Ex Vivo, In Vivo, Using Cells, Animal Tissues, and Alternative Models 205
12 Biological and Computational Techniques to Identify Mitochondrial Toxicants 207
13 The Parallel Testing of Isolated Rat Liver and Kidney Mitochondria Reveals a Calcium?]Dependent Sensitivity to Diclofenac and Ibuprofen 217
14 In Vitro Methodologies to Investigate Drug?]Induced Toxicities 229
15 Combined Automated Measurement of Respiratory Chain Complexes and Oxidative Stress: A First Step to an Integrated View of Cell Bioenergetics 249
16 Measurement of Mitochondrial Toxicity by Flow Cytometry 265
17 MitoChip: A Transcriptomics Tool for Elucidation of Mechanisms of Mitochondrial Toxicity 275
18 Using 3D Microtissues for Identifying Mitochondrial Liabilities 295
19 Toward Mitochondrial Medicine: Challenges in Rodent Modeling of Human Mitochondrial Dysfunction 305
20 Measurement of Oxygen Metabolism In Vivo 315
21 Detection of Mitochondrial Toxicity Using Zebrafish 323
22 MiRNA as Biomarkers of Mitochondrial Toxicity 347
23 Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and Beyond 373
24 Acylcarnitines as Translational Biomarkers of Mitochondrial Dysfunction 383
25 Mitochondrial DNA as a Potential Translational Biomarker of Mitochondrial Dysfunction in Drug?]Induced Toxicity Studies 395
26 Predicting Off?]Target Effects of Therapeutic Antiviral Ribonucleosides: Inhibition of Mitochondrial RNA Transcription 407
27 Imaging of Mitochondrial Toxicity in the Kidney 419
28 Imaging Mitochondrial Membrane Potential and Inner Membrane Permeability 429
29 Quantifying Skeletal Muscle Mitochondrial Function In Vivo by 31P Magnetic Resonance Spectroscopy 443

Volume 2
• Part 4 Reports from the Clinic 457
30 Statin and Fibrate?]Induced Dichotomy of Mitochondrial Function 459
31 Friend or Foe: Can Mitochondrial Toxins Lead to Similar Benefits as Exercise? 475
32 Involvement of Mitochondrial Dysfunction on the Toxic Effects Caused by Drugs of Abuse and Addiction 487
33 Drug?]Induced Mitochondrial Toxicity during Pregnancy 509
34 Mitochondrial Toxicity in Children and Adolescents Exposed to Antiretroviral Therapy 521
35 Drug?]Induced Mitochondrial Cardiomyopathy and Cardiovascular Risks in Children 529
36 Role of Mitochondrial Dysfunction in Linezolid?]Induced Lactic Acidosis 547
37 Metformin and Lactic Acidosis 559
38 Lessons Learned from a Phase I Clinical Trial of Mitochondrial Complex I Inhibition 563
39 Pharmacological Activation of Mitochondrial Biogenesis for the Treatment of Various Pathologies 569
40 Mitochondrial Toxicity Induced by Chemotherapeutic Drugs 593
• Part 5 Environmental Toxicants and Mitochondria 613
41 The Mitochondrial Exposome 615
42 Central Mitochondrial Signaling Mechanisms in Response to Environmental Agents: Integrated Omics for Visualization 639
43 Detection of Mitochondrial Toxicity of Environmental Pollutants Using Caenorhabditis elegans 655
44 Persistent Organic Pollutants, Mitochondrial Dysfunction, and Metabolic Syndrome 691
45 Cigarette Smoke and Mitochondrial Damage 709
Index 727

Developed as a one-stop reference source for drug safety and toxicology professionals, this book explains why mitochondrial failure is a crucial step in drug toxicity and how it can be avoided.

• Covers both basic science and applied technology / methods
• Allows readers to understand the basis of mitochondrial function, the preclinical assessments used, and what they reveal about drug effects
• Contains both in vitro and in vivo methods for analysis, including practical screening approaches for drug discovery and development
• Adds coverage about mitochondrial toxicity underlying organ injury, clinical reports on drug classes, and discussion of environmental toxicants affecting mitochondria

• Yvonne Will, PhD, is a Senior Director and the Head of Science and Technology Strategy, Drug Safety Research and Development at Pfizer, Connecticut, USA. In addition to the prior edition of this book, she co-edited Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers(Wiley, 2016).
• James A. Dykens, PhD, oversees EyeCyte Therapeutics, a start-up developing treatments for progressive blinding diseases via targeting mitochondrial dysfunction. He co-edited the first edition of this book.