Mechanistic Toxicology

Transcription

1 SECOND EDITION Mechanistic Toxicology The Molecular Basis of How Chemicals Disrupt Biological Targets URS A. BOELSTERLI CRC Press Tavlor & France Croup CRC Press is an imp^t o* :H Taylor H Francn C'r,,jpi a".

2 Contents Chapter 1 Introduction Why molecular mechanisms? Toxicokinetics and toxicodynamics Toxicokinetic factors as basic mechanisms of toxicity Toxicodynamic factors as basic mechanisms of toxicity 7 Learning points 12 Further reading 13 Chapter 2 Types of Toxic Responses Adaptation to cellular stress Toxic responses Disruption of cytoprotective mechanisms 19 Learning points 21 Further reading 22 Chapter 3 Organ-Selective Toxicity Biological basis of organ-selective toxicity Molecular homology Tissue-selective transcription factors Tissue-restricted expression of molecular targets Selective hepatotoxicity and nephrotoxicity Xenobiotic-bioactiving enzymes Vectorial transport of xenobiotics 33 Learning points 36 Further reading 37 Chapter 4 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 Multispecific hepatic bile salt uptake systems Pulmonary epithelial-cell polyamine carrier The neuronal dopamine transporter and xenobiotic-induced Parkinsonism Xenobiotic export pumps 48

3 4.3.1 Hepatobiliary conjugate export pump and cholestasis Multidrug resistance in cancer cells Permeability of the blood-brain barrier and blood-testis barrier 54 Learning points 58 Further reading 58 Chapter 5 Bioactivation of Xenobiotics to Reactive Metabolites Biotransformation and bioactivation/bioinactivation Phase I (functionalization) and phase II (conjugation) reactions Cytochrome P450 (CYP) Mechanisms and toxicological consequences of isoform-selective CYP induction Mechanisms and consequences of isoform-selective CYP inhibition Bioactivation of xenobiotics by CYP Peroxidases UDP-glucuronosyltransferase (UGT) Mechanisms and toxicological consequences of UGT induction Reactive acyl glucuronides and their positional isomers (V-glucuronidation of aromatic amines Sulfotransferase (SULT) /V-acetyltransferase (NAT) Bioactivation of arylamines Toxicological consequences of individual NAT expression Glutathione-S-transferase (GST) Glutathione conjugation as a protective mechanism Bioactivation of xenobiotics by GST Net balance of bioactivation/bioinactivation for risk assessment Mechanisms of phototoxicity Protective mechanisms against reactive metabolites: the stress response Induction of heat-shock proteins Targeting of stress-response proteins by reactive metabolites 109 Learning points 110 Further reading 111 Chapter 6 Xenobiotic-Induced Oxidative Stress: Cell Injury, Signaling, and Gene Regulation Reactive oxygen species (ROS) and oxidoreductive stress 117

4 6.1.1 Mechanisms of xenobiotic-induced intracellular ROS production The key players: superoxide anion radical, hydrogen peroxide, and hydroxyl radical Role of iron and other redox-active transition metals Mechanisms of xenobiotic-enhanced extracellular ROS production Other ROS: ozone and singlet oxygen Reactive nitrogen species (RNS) and oxidative stress Toxicological consequences of oxidative stress Oxidative DNA damage Oxidative protein damage Oxidative lipid damage Interference with antioxidant defense mechanisms Glutathione GSH-coupled enzyme systems Genetic deficiency in erythrocyte glucose-6-phosphate dehydrogenase Superoxide dismutase Metallothionein a-tocopherol Intracellular signaling and gene regulation by oxidative stress 161 Learning points 169 Further reading 169 Chapter 7 Disruption of Cellular Calcium Homeostasis Xenobiotic-induced alterations in intracellular Ca 2+ distribution Toxicological consequences of increased cytosolic Ca :+ concentrations 179 Learning points 183 Further reading 184 Chapter 8 Mechanisms of Necrotic and Apoptotic Cell Death Necrosis Mechanisms of necrosis Initiation and progression of necrotic tissue injury Apoptosis Molecular mechanisms and pathways of apoptosis Molecular mechanisms of apoptotic cell death (I Molecular mechanisms of apoptotic cell death (II) Signaling through death receptors Caspases the executors Role of mitochondria Checkpoints the Bcl-2 proteins 201

5 8.2.6 Suppression of apoptosis toxicological consequences 203 Learning points 204 Further reading 205 Chapter 9 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 215 Learning points 218 Further reading 219 Chapter 10 Covalent Binding of Reactive Metabolites to Cellular Macromolecules Electrophiles and nucleophilic targets Covalent protein binding Selectivity of covalent adduct formation Downstream toxicological consequences of covalent protein binding Covalent modification and inactivation of protein phosphatases Covalent modification of neurofilaments Covalent modification of proteins in the biliary tree and small intestine Covalent DNA binding Toxicological consequences of DNA alkylation 243 Learning points 245 Further reading 246 Chapter 11 Immune Mechanisms Xenobiotic-induced activation of the innate immune system Immunosuppression by xenobiotics Immune-mediated toxicity Autoimmune reactions Immunoallergy Idiosyncratic reactions and the "danger" hypothesis 274 Learning points 276 Further reading 277 Chapter 12 Cytokine-Mediated Toxicity Tumor necrosis factor-a and other proinflammatory cytokines 282

6 12.2 Chemokines and inflammatory cell recruitment 285 Learning points 287 Further reading 288 Chapter 13 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 296 Learning points 298 Further reading 299 Chapter 14 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 305 Learning points 307 Further reading 308 Chapter 15 Nuclear Receptor-Mediated Toxicity The aryl hydrocarbon receptor (AHR) AHR-mediated toxicity of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls Xenoestrogens and antiandrogens Estrogen-receptor (ER)-mediated toxicity Androgen receptor (AR)-mediated toxicity Peroxisome proliferator-activated receptors (PPARs) PPARa-dependent toxicity PPARy-mediated toxicity Retinoic acid receptor (RAR) 332 Learning points 334 Further reading 335 Chapter 16 Activation or Disruption of Cellular Signal Transduction by Xenobiotics Signaling: sensing and responding The receptors The signaling pathways Interference with signal transduction by xenobiotics Disruption of G-protein-coupled receptor function Protein kinase signaling pathways 347

7 Multiple activation of protein kinase signaling pathways Activation of protein kinase signal transduction pathways by "foreign" signaling pathways Activation of protein kinase pathways by inactivation of phosphatases Inactivation of selective MAPK signal transduction pathways Activation and inactivation of JNK and its role in mitochondria-mediated cell death Disruption of sensor (transcription factor) function 353 Learning points 355 Further reading 355 Chapter 17 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 mitochondrial fatty acyl (3-oxidation Xenobiotics as pseudosubstrates for the citrate cycle Inhibition of the electron transport chain and increased generation of ROS Mitochondrial membrane permeabilization Induction of the mitochondrial outer-membrane permeabilization (MOMP) Opening of the mitochondrial membrane permeability transition (mpt) pore Selective depletion of mitochondrial DNA 377 Learning points 380 Further reading 381 Chapter 18 Novel Mechanisms Derived from Systems Toxicology 385 Learning points 389 Further reading 389 Index 391