Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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

Auteur

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.

Texte du rabat

A major public health concern, despite regulatory vigilance, is untoward toxicity and other pharmaceutical side effects. This toxicity is often idiosyncratic, and usually not discovered until after a large population has been exposed and injured. Recent laboratory evaluations show that many of these drugs impact mitochondrial function. The realization that mitochondrial toxicity is a widespread and important issue in drug toxicity is increasingly appreciated, and most pharmaceutical companies now either have the technology to assess this risk themselves, or do so via contract research organizations.

Developed as a one-stop reference source for drug safety and toxicology professionals, the second edition of Drug and Environmental Induced Mitochondrial Dysfunction explains why mitochondrial failure is a crucial step in drug toxicity and how it can be avoided. It allows readers to understand the basis of mitochondrial function and the preclinical assessments used and what they reveal about drug effects. The focus is on how the requisite technology continues to evolve and the recent emergence of clinical techniques capable of detecting drug-induced mitochondrial toxicity in patients.

Added coverage in the 2nd edition includes how and why mitochondrial toxicity underlies organ injury, clinical reports on drug classes, and discussion of environmental toxicants that can affect mitochondria. With chapters contributed by leading specialists in their areas, Drug and Environmental Induced Mitochondrial Dysfunction, 2nd Edition continues to serve as a valuable resource for safety assessment professionals in the pharmaceutical industry including bench scientists and managers and for pharmacologists and toxicologists in both drug and environmental health sciences.

Drug and Environmental Induced Mitochondrial Dysfunction provides ample reminders of the intimate connections between mitochondria, pharmacology, and toxicology. The book takes a rather systematic approach to mitochondrial pharmacology and toxicology and, for this reason, will be of use to even those outside of strict drug discovery.

Contenu

Volume 1

List of Contributors xvii

Foreword xxix

Part 1 Basic Concepts 1

1 Contributions of Plasma Protein Binding and Membrane Transporters to Drug?]Induced Mitochondrial Toxicity 3
Gavin P. McStay

2 The Role of Transporters in Drug Accumulation and Mitochondrial Toxicity 15
Kathleen M. Giacomini and Huan?]Chieh Chien

3 StructureActivity Modeling of Mitochondrial Dysfunction 25
Steve Enoch, Claire Mellor, and Mark Nelms

4 Mitochondria?]Targeted Cytochromes P450 Modulate Adverse Drug Metabolism and Xenobiotic Induced Toxicity 35
Haider Raza, F. Peter Guengerich, and Narayan G. Avadhani

Part 2 Organ Drug Toxicity: Mitochondrial Etiology 47

5 Mitochondrial Dysfunction in Drug?]Induced Liver Injury 49
Annie Borgne?]Sanchez and Bernard Fromenty

6 Evaluating Mitotoxicity as Either a Single or Multi?]Mechanistic Insult in the Context of Hepatotoxicity 73
Amy L. Ball, Laleh Kamalian, Carol E. Jolly, and Amy E. Chadwick

7 Cardiotoxicity of Drugs: Role of Mitochondria 93
Zoltan V. Varga and Pal Pacher

8 Skeletal Muscle Mitochondrial Toxicity 111
Eric K. Herbert, Saul R. Herbert, and Karl E. Herbert

9 Manifestations of Drug Toxicity on Mitochondria in the Nervous System 133
Jochen H. M. Prehn and Irene Llorente?]Folch

10 Nephrotoxicity: Increasing Evidence for a Key Role of Mitochondrial Injury and Dysfunction and Therapeutic Implications 169
Ana Belén Sanz, Maria Dolores Sanchez?]Niño, Adrian M. Ramos, and Alberto Ortiz

11 Mammalian Sperm Mitochondrial Function as Affected by Environmental Toxicants, Substances of Abuse, and Other Chemical Compounds 185
Sandra Amaral, Renata S. Tavares, Sara Escada?]Rebelo, Andreia F. Silva, and João Ramalho?]Santos

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
Robert B. Cameron, Craig C. Beeson, and Rick G. Schnellmann

13 The Parallel Testing of Isolated Rat Liver and Kidney Mitochondria Reveals a Calcium?]Dependent Sensitivity to Diclofenac and Ibuprofen 217
Sabine Schulz, Sabine Borchard, Tamara Rieder, Carola Eberhagen, Bastian Popper, Josef Lichtmannegger, Sabine Schmitt, and Hans Zischka

14 In Vitro Methodologies to Investigate Drug?]Induced Toxicities 229
Rui F. Simões, Teresa Cunha?]Oliveira, Cláudio F. Costa, Vilma A. Sardão, and Paulo J. Oliveira

15 Combined Automated Measurement of Respiratory Chain Complexes and Oxidative Stress: A First Step to an Integrated View of Cell Bioenergetics 249
Marc Conti, Thierry Delvienne, and Sylvain Loric

16 Measurement of Mitochondrial Toxicity by Flow Cytometry 265
Padma Kumar Narayanan and Nianyu Li

17 MitoChip: A Transcriptomics Tool for Elucidation of Mechanisms of Mitochondrial Toxicity 275
Varsha G. Desai, and G. Ronald Jenkins

18 Using 3D Microtissues for Identifying Mitochondrial Liabilities 295
Simon Messner, Olivier Frey, Katrin Rössger, Andy Neilson, and Jens M. Kelm

19 Toward Mitochondrial Medicine: Challenges in Rodent Modeling of Human Mitochondrial Dysfunction 305
David A. Dunn, Michael H. Irwin, Walter H. Moos, Kosta Steliou, and Carl A. Pinkert

20 Measurement of Oxygen Metabolism In Vivo 315
M. P. J. van Diemen, R. Ubbink, F. M. Münker, E. G. Mik, and G. J. Groeneveld

21 Detection of Mitochondrial Toxicity Using Zebrafish 323
Sherine S. L. Chan and Tucker Williamson

22 MiRNA as Biomarkers of Mitochondrial Toxicity 347
Terry R. Van Vleet and Prathap Kumar Mahalingaiah

23 Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and Beyond 373
Benjamin L. Woolbright and Hartmut Jaeschke <p&...