Drug-Induced Mitochondrial Dysfunction

by Dykens, James A.; Will, Yvonne

• ISBN13: 9780470111314
• ISBN10: 0470111313
• Edition: 1st
• Format: Hardcover
• Copyright: 2008-09-22
• Publisher: Wiley-Interscience

Summary

This is the definitive, one-stop resource on preclinical drug evaluation for potential mitochondrial toxicity, addressing the issue upfront in the drug development process. It discusses mitochondrial impairment to organs, skeletal muscle, and nervous systems and details methodologies used to assess mitochondria function. It covers both in vitro and in vivo methods for analysis and includes the latest models. This is the authoritative reference on drug-induced mitochondrial dysfunction for safety assessment professionals in the pharmaceutical industry and for pharmacologists and toxicologists in both drug and environmental health sciences.

Author Biography

James A. Dykens, PhD, is an Associate Research Fellow in Pfizer's Drug Safety Research and Development Department. Currently in Sandwich, England, he previously worked in a similar role with Pfizer in La Jolla, California. Prior to his work with Pfizer, Dr. Dykens was the senior director of technology development for MIGENIX Inc., a senior scientist and the director of business development at MitoKor, Inc., and a senior principal scientist at Parke-Davis Pharmaceutical Research. Dr. Dykens has published extensively on drug-induced mitochondrial dysfunction, on the role of mitochondrial free radical production in the etiology of neurodegenerative diseases, and on the physiological ecology of marine symbioses.

Yvonne Will, PhD, works in Pfizer's Exploratory Safety Differentiation Group in Groton, Connecticut. Prior to this position, she led Pfizer's Investigative Biochemical Toxicity Group within the Drug Safety Research and Development Department in La Jolla. Before joining Pfizer, Dr. Will worked on mitochondrial proteomics and physiology at MitoKor, Inc. Dr. Will has authored a host of articles and book chapters. She is a member of the Society of Toxicology and a frequent speaker for groups like ACT and World Pharmaceutical Congress.

Table of Contents

Contributors	p. ix
Preface	p. xiii
Basic Concepts	p. 1
Basic Mitochondrial Physiology in Cell Viability and Death	p. 3
Basic Molecular Biology of Mitochondrial Replication	p. 37
Drug-Associated Mitochondrial Toxicity	p. 71
Pharmacogenetics of Mitochondrial Drug Toxicity	p. 127
Organ Drug Toxicity: Mitochondrial Etiology	p. 141
Features and Mechanisms of Drug-Induced Liver Injury	p. 143
Cardiovascular Toxicity of Mitochondrial Origin	p. 203
Skeletal Muscle and Mitochondrial Toxicity	p. 235
Manifestations of Drug Toxicity on Mitochondria in the Nervous System	p. 251
Lipoatrophy and Other Manifestations of Antiretroviral Therapeutics	p. 273
Nephrotoxicity	p. 291
Drug Effects in Patients with Mitochondrial Diseases	p. 311
Assessment of Mitochondrial Function in Vitro and in Vivo	p. 325
Polarographic Oxygen Sensors, the Oxygraph, and High-Resolution Respirometry to Assess Mitochondrial Function	p. 327
Use of Oxygen-Sensitive Fluorescent Probes for the Assessment of Mitochondrial Function	p. 353
Mitochondrial Dysfunction Assessed Quantitatively in Real Time by Measuring the Extracellular Flux of Oxygen and Protons	p. 373
Assessment of Mitochondrial Respiratory Complex Function In Vitro and In Vivo	p. 383
OXPHOS Complex Activity Assays and Dipstick Immunoassays for Assessment of OXPHOS Protein Levels	p. 397
Use of Fluorescent Reporters to Measure Mitochondrial Membrane Potential and the Mitochondrial Permeability Transition	p. 413
Compartmentation of Redox Signaling and Control: Discrimination of Oxidative Stress in Mitochondria, Cytoplasm, Nuclei, and Endoplasmic Reticulum	p. 433
Assessing Mitochondrial Protein Synthesis in Drug Toxicity Screening	p. 463
Mitochondrial Toxicity of Antiviral Drugs: A Challenge to Accurate Diagnosis	p. 473
Clinical Assessment of Mitochondrial Function via [superscript 13 C]Methionine Exhalation	p. 493
Assessment of Mitochondrial Dysfunction by Microscopy	p. 507
Development of Animal Models of Drug-Induced Mitochondrial Toxicity	p. 539
Noninvasive Assessment of Mitochondrial Function Using Nuclear Magnetic Resonance Spectroscopy	p. 555
Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations	p. 575
Index	p. 589
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