2nd Edition

Mechanistic Toxicology The Molecular Basis of How Chemicals Disrupt Biological Targets, Second Edition

By Urs A. Boelsterli Copyright 2007
    416 Pages 210 B/W Illustrations
    by CRC Press

    416 Pages
    by CRC Press

    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

  • Updated chapters
  • Types of toxic responses
  • Disruption of signal transduction by xenobiotics
  • Disruption of mitochondrial function
  • Novel mechanisms derived from systems toxicology
  • Introduction
    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
    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


    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