2nd Edition
Mechanistic Toxicology The Molecular Basis of How Chemicals Disrupt Biological Targets, Second Edition
A thorough understanding of cellular and molecular mechanisms involved in the individual expression of toxic effects provides an important tool for assessment of human health risk. New aspects, major advances, and new areas in molecular and cellular biology and toxicology demand updated sources of information to elucidate the functional mechanics of human toxicology.
Mechanistic Toxicology: The Molecular Basis of How Chemicals Disrupt Biological Targets, Second Edition retains the accessible format of the original to present the general principles that link xenobiotic-induced toxicity with the molecular pathways that underlie these toxic effects. Extensively illustrated, this book forms a conceptual bridge between multiple events at the molecular level and the determinants of toxicity at the physiological and cellular level. Specific examples of drugs, environmental pollutants, and other chemicals are carefully chosen to illustrate and highlight the fundamental mechanisms of toxicity at different toxicokinetic and toxicodynamic levels. The book includes references and review articles at the end of each chapter, as well as boxed text for relevant review information on biological, biochemical, molecular, and toxicological background. Linking molecular pathways to more general biomedical contexts, the author ensures that the reader is not lost in the details and instead receives a broad understanding of the processes underlying xenobiotic toxicity.
New in the Second Edition
Why Molecular Mechanisms?
Toxicokinetics and Toxicodynamics
Types of Toxic Responses
Adaptation to Cellular Stress
Toxic Responses
Disruption of Cytoprotective Mechanisms
Organ-Selective Toxicity
Biological Basis of Organ-Selective Toxicity
Selective Hepatotoxicity and Nephrotoxicity
Cellular Transport and Selective Accumulation of Potentially Toxic Xenobiotics
Transmembrane Transport of Xenobiotics
Cell-Specific Delivery of Xenobiotics to Intracellular Targets by Physiological Uptake Systems
Xenobiotic Export Pumps
Bioactivation of Xenobiotics to Reactive Metabolites
Biotransformation and Bioactivation/-Inactivation
Phase I (Functionalization) and Phase II (Conjugation) Reactions
Net Balance of Bioactivation/Bioinactivation for Risk Assessment
Mechanisms of Phototoxicity
Protective Mechanisms Against Reactive Metabolites: The Stress Response
Xenobiotic-Induced Oxidative Stress: Cell Injury, Signaling, and Gene Regulation
Reactive Oxygen Species (ROS) and Oxidoreductive Stress
Toxicological Consequences of Oxidative Stress
Interference with Antioxidant Defense Mechanisms
Intracellular Signaling and Gene Regulation by Oxidative Stress
Disruption of Cellular Calcium Homeostasis
Xenobiotic-Induced Alterations in Intracellular Ca2+ Distribution
Toxicological Consequences of Increased Cytosolic Ca2+ Concentrations
Mechanisms of Necrotic and Apoptotic Cell Death
Necrosis
Apoptosis
Impairment of Cell Proliferation and Tissue Repair
The Cell Cycle
Stimulation of DNA Synthesis and Cell Proliferation: Xenobiotics as Mitogens
Inhibition of Cell Proliferation by Xenobiotics
Inhibition of Tissue Repair
Covalent Binding of Reactive Metabolites to Cellular Macromolecules
Electrophiles and Nucleophilic Targets
Covalent Protein Binding
Covalent DNA Binding
Immune Mechanisms
Xenobiotic-Induced Activation of the Innate Immune System
Immunosuppression by Xenobiotics
Immune-Mediated Toxicity
Cytokine-Mediated Toxicity
Tumor Necrosis Factor-a and Other Proinflammatory Cytokines
Chemokines and Inflammatory Cell Recruitment
Specific Inactivation of Enzymes and Other Proteins
Inactivation of Thiol-Containing Enzymes
Disruption of Acetylcholinesterase Activity
Transthyretin Binding and Inactivation: Disruption of Thyroid Function
Inactivation of DNA-mismatch-repair Proteins
Interactions of Xenobiotics with Ion Transporters
Interactions with Neuronal Na+ Channels
Interactions with the Na+/K+ Pump
Selective Inhibition of Cardiac Myocyte K+ Channels and QT Prolongation
Nuclear Receptor-Mediated Toxicity
The Aryl Hydrocarbon Receptor (AHR)
Xenoestrogens and Antiandrogens
Peroxisome Proliferator-Activated Receptors (PPARs)
Retinoic Acid Receptor (RAR)
Activation or Disruption of Cellular Signal Transduction by Xenobiotics
Signaling: Sensing and Responding
Interference with Signal Transduction by Xenobiotics
Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity
Mitochondrial Targets and Xenobiotic-Induced Bioenergy Crisis
Protonophoretic and Uncoupling Activity of Xenobiotics
Inhibition of NADH Production
Inhibition of the Electron Transport Chain and Increased Generation of ROS
Mitochondrial Membrane Permeabilization
Selective Depletion of Mitochondrial DNA
Novel Mechanisms Derived from Systems Toxicology
Index
Biography
Urs A. Boelsterli
'Students taking formal training in toxicology would definitely benefit from adding this book to their collection, since it covers many recent advances in the field.' - British Toxicology Society Newsletter
'This recently-published volume is a clear state-of-the-art explanation and description of how chemicals disrupt biological targets on a molecular basis. It is a beauty!'. - Toxicology Letters
