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".
Contents Chapter 1 Introduction 1 1.1 Why molecular mechanisms? 1 1.2 Toxicokinetics and toxicodynamics 5 1.2.1 Toxicokinetic factors as basic mechanisms of toxicity 6 1.2.2 Toxicodynamic factors as basic mechanisms of toxicity 7 Learning points 12 Further reading 13 Chapter 2 Types of Toxic Responses 15 2.1 Adaptation to cellular stress 16 2.2 Toxic responses 18 2.3 Disruption of cytoprotective mechanisms 19 Learning points 21 Further reading 22 Chapter 3 Organ-Selective Toxicity 23 3.1 Biological basis of organ-selective toxicity 23 3.1.1 Molecular homology 23 3.1.2 Tissue-selective transcription factors 25 3.1.3 Tissue-restricted expression of molecular targets 27 3.2 Selective hepatotoxicity and nephrotoxicity 31 3.2.1 Xenobiotic-bioactiving enzymes 32 3.2.2 Vectorial transport of xenobiotics 33 Learning points 36 Further reading 37 Chapter 4 Cellular Transport and Selective Accumulation of Potentially Toxic Xenobiotics 39 4.1 Transmembrane transport of xenobiotics 39 4.2 Cell-specific delivery of xenobiotics to intracellular targets by physiological uptake systems 41 4.2.1 Multispecific hepatic bile salt uptake systems 41 4.2.2 Pulmonary epithelial-cell polyamine carrier 42 4.2.3 The neuronal dopamine transporter and xenobiotic-induced Parkinsonism 45 4.3 Xenobiotic export pumps 48
4.3.1 Hepatobiliary conjugate export pump and cholestasis 49 4.3.2 Multidrug resistance in cancer cells 52 4.3.3 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 63 5.1 Biotransformation and bioactivation/bioinactivation 63 5.2 Phase I (functionalization) and phase II (conjugation) reactions 64 5.2.1 Cytochrome P450 (CYP) 65 5.2.1.1 Mechanisms and toxicological consequences of isoform-selective CYP induction 71 5.2.1.2 Mechanisms and consequences of isoform-selective CYP inhibition 74 5.2.1.3 Bioactivation of xenobiotics by CYP 76 5.2.2 Peroxidases 78 5.2.3 UDP-glucuronosyltransferase (UGT) 79 5.2.3.1 Mechanisms and toxicological consequences of UGT induction 82 5.2.3.2 Reactive acyl glucuronides and their positional isomers 82 5.2.3.3 (V-glucuronidation of aromatic amines 83 5.2.4 Sulfotransferase (SULT) 86 5.2.5 /V-acetyltransferase (NAT) 88 5.2.5.1 Bioactivation of arylamines 89 5.2.5.2 Toxicological consequences of individual NAT expression 90 5.2.6 Glutathione-S-transferase (GST) 93 5.2.6.1 Glutathione conjugation as a protective mechanism 93 5.2.6.2 Bioactivation of xenobiotics by GST 95 5.3 Net balance of bioactivation/bioinactivation for risk assessment 101 5.4 Mechanisms of phototoxicity 104 5.5 Protective mechanisms against reactive metabolites: the stress response 107 5.5.1 Induction of heat-shock proteins 108 5.5.2 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 117 6.1 Reactive oxygen species (ROS) and oxidoreductive stress 117
6.1.1 Mechanisms of xenobiotic-induced intracellular ROS production 119 6.1.2 The key players: superoxide anion radical, hydrogen peroxide, and hydroxyl radical 125 6.1.3 Role of iron and other redox-active transition metals 128 6.1.4 Mechanisms of xenobiotic-enhanced extracellular ROS production 132 6.1.5 Other ROS: ozone and singlet oxygen 134 6.1.6 Reactive nitrogen species (RNS) and oxidative stress 136 6.2 Toxicological consequences of oxidative stress 138 6.2.1 Oxidative DNA damage 139 6.2.2 Oxidative protein damage... 142 6.2.3 Oxidative lipid damage 145 6.3 Interference with antioxidant defense mechanisms 149 6.3.1 Glutathione 150 6.3.1.1 GSH-coupled enzyme systems 151 6.3.1.2 Genetic deficiency in erythrocyte glucose-6-phosphate dehydrogenase 153 6.3.2 Superoxide dismutase 157 6.3.3 Metallothionein 158 6.3.4 a-tocopherol 161 6.4 Intracellular signaling and gene regulation by oxidative stress 161 Learning points 169 Further reading 169 Chapter 7 Disruption of Cellular Calcium Homeostasis 177 7.1 Xenobiotic-induced alterations in intracellular Ca 2+ distribution 177 7.2 Toxicological consequences of increased cytosolic Ca :+ concentrations 179 Learning points 183 Further reading 184 Chapter 8 Mechanisms of Necrotic and Apoptotic Cell Death 185 8.1 Necrosis 185 8.1.1 Mechanisms of necrosis 185 8.1.2 Initiation and progression of necrotic tissue injury 186 8.2 Apoptosis 187 8.2.1 Molecular mechanisms and pathways of apoptosis 187 8.2.1.1 Molecular mechanisms of apoptotic cell death (I 188 8.2.1.2 Molecular mechanisms of apoptotic cell death (II) 191 8.2.2 Signaling through death receptors 192 8.2.3 Caspases the executors 196 8.2.4 Role of mitochondria 198 8.2.5 Checkpoints the Bcl-2 proteins 201
8.2.6 Suppression of apoptosis toxicological consequences 203 Learning points 204 Further reading 205 Chapter 9 Impairment of Cell Proliferation and Tissue Repair 209 9.1 The cell cycle 209 9.2 Stimulation of DNA synthesis and cell proliferation: xenobiotics as mitogens 210 9.3 Inhibition of cell proliferation by xenobiotics 213 9.4 Inhibition of tissue repair 215 Learning points 218 Further reading 219 Chapter 10 Covalent Binding of Reactive Metabolites to Cellular Macromolecules 221 10.1 Electrophiles and nucleophilic targets 221 10.2 Covalent protein binding 223 10.2.1 Selectivity of covalent adduct formation 224 10.2.2 Downstream toxicological consequences of covalent protein binding 228 10.2.2.1 Covalent modification and inactivation of protein phosphatases 229 10.2.2.2 Covalent modification of neurofilaments 233 10.2.2.3 Covalent modification of proteins in the biliary tree and small intestine 238 10.3 Covalent DNA binding 242 10.3.1 Toxicological consequences of DNA alkylation 243 Learning points 245 Further reading 246 Chapter 11 Immune Mechanisms 251 11.1 Xenobiotic-induced activation of the innate immune system 252 11.2 Immunosuppression by xenobiotics 256 11.3 Immune-mediated toxicity 260 11.3.1 Autoimmune reactions 265 11.3.2 Immunoallergy 267 11.3.3 Idiosyncratic reactions and the "danger" hypothesis 274 Learning points 276 Further reading 277 Chapter 12 Cytokine-Mediated Toxicity 281 12.1 Tumor necrosis factor-a and other proinflammatory cytokines 282
12.2 Chemokines and inflammatory cell recruitment 285 Learning points 287 Further reading 288 Chapter 13 Specific Inactivation of Enzymes and Other Proteins 289 13.1 Inactivation of thiol-containing enzymes 289 13.2 Disruption of acetylcholinesterase activity 289 13.3 Transthyretin binding and inactivation: disruption of thyroid function 294 13.4 Inactivation of DNA-mismatch-repair proteins 296 Learning points 298 Further reading 299 Chapter 14 Interactions of Xenobiotics with Ion Transporters 301 14.1 Interactions with neuronal Na + channels 301 14.2 Interactions with the Na + /K + pump 303 14.3 Selective inhibition of cardiac myocyte K + channels and QT prolongation 305 Learning points 307 Further reading 308 Chapter 15 Nuclear Receptor-Mediated Toxicity 309 15.1 The aryl hydrocarbon receptor (AHR) 310 15.1.1 AHR-mediated toxicity of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls 311 15.2 Xenoestrogens and antiandrogens 317 15.2.1 Estrogen-receptor (ER)-mediated toxicity 318 15.2.2 Androgen receptor (AR)-mediated toxicity 321 15.3 Peroxisome proliferator-activated receptors (PPARs) 324 15.3.1 PPARa-dependent toxicity 326 15.3.2 PPARy-mediated toxicity 328 15.4 Retinoic acid receptor (RAR) 332 Learning points 334 Further reading 335 Chapter 16 Activation or Disruption of Cellular Signal Transduction by Xenobiotics 341 16.1 Signaling: sensing and responding 341 16.1.1 The receptors 342 16.1.2 The signaling pathways 343 16.2 Interference with signal transduction by xenobiotics 345 16.2.1 Disruption of G-protein-coupled receptor function 346 16.2.2 Protein kinase signaling pathways 347
16.2.2.1 Multiple activation of protein kinase signaling pathways 347 16.2.2.2 Activation of protein kinase signal transduction pathways by "foreign" signaling pathways 347 16.2.2.3 Activation of protein kinase pathways by inactivation of phosphatases 348 16.2.2.4 Inactivation of selective MAPK signal transduction pathways 349 16.2.2.5 Activation and inactivation of JNK and its role in mitochondria-mediated cell death 350 16.2.3 Disruption of sensor (transcription factor) function 353 Learning points 355 Further reading 355 Chapter 17 Disruption of Mitochondrial Function and Mitochondria- Mediated Toxicity 357 17.1 Mitochondrial targets and xenobiotic-induced bioenergy crisis 357 17.2 Protonophoretic and uncoupling activity of xenobiotics 360 17.3 Inhibition of NADH production 362 17.3.1 Inhibition of mitochondrial fatty acyl (3-oxidation 362 17.3.2 Xenobiotics as pseudosubstrates for the citrate cycle 365 17.4 Inhibition of the electron transport chain and increased generation of ROS 366 17.5 Mitochondrial membrane permeabilization 372 17.5.1 Induction of the mitochondrial outer-membrane permeabilization (MOMP) 372 17.5.2 Opening of the mitochondrial membrane permeability transition (mpt) pore 372 17.6 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