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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

Tabla de contenidos provista por Syndetics

• Chapter 1 Introduction(p. 1)
• 1.1 Why molecular mechanisms?(p. 1)
• 1.2 Toxicokinetics and toxicodynamics(p. 5)
• 1.2.1 Toxicokinetic factors as basic mechanisms of toxicity(p. 6)
• 1.2.2 Toxicodynamic factors as basic mechanisms of toxicity(p. 7)
• Learning points(p. 12)
• Further reading(p. 13)
• Chapter 2 Types of Toxic Responses(p. 15)
• 2.1 Adaptation to cellular stress(p. 16)
• 2.2 Toxic responses(p. 18)
• 2.3 Disruption of cytoprotective mechanisms(p. 19)
• Learning points(p. 21)
• Further reading(p. 22)
• Chapter 3 Organ-Selective Toxicity(p. 23)
• 3.1 Biological basis of organ-selective toxicity(p. 23)
• 3.1.1 Molecular homology(p. 23)
• 3.1.2 Tissue-selective transcription factors(p. 25)
• 3.1.3 Tissue-restricted expression of molecular targets(p. 27)
• 3.2 Selective hepatotoxicity and nephrotoxicity(p. 31)
• 3.2.1 Xenobiotic-bioactiving enzymes(p. 32)
• 3.2.2 Vectorial transport of xenobiotics(p. 33)
• Learning points(p. 36)
• Further reading(p. 37)
• Chapter 4 Cellular Transport and Selective Accumulation of Potentially Toxic Xenobiotics(p. 39)
• 4.1 Transmembrane transport of xenobiotics(p. 39)
• 4.2 Cell-specific delivery of xenobiotics to intracellular targets by physiological uptake systems(p. 41)
• 4.2.1 Multispecific hepatic bile salt uptake systems(p. 41)
• 4.2.2 Pulmonary epithelial-cell polyamine carrier(p. 42)
• 4.2.3 The neuronal dopamine transporter and xenobiotic-induced Parkinsonism(p. 45)
• 4.3 Xenobiotic export pumps(p. 48)
• 4.3.1 Hepatobiliary conjugate export pump and cholestasis(p. 49)
• 4.3.2 Multidrug resistance in cancer cells(p. 52)
• 4.3.3 Permeability of the blood-brain barrier and blood-testis barrier(p. 54)
• Learning points(p. 58)
• Further reading(p. 58)
• Chapter 5 Bioactivation of Xenobiotics to Reactive Metabolites(p. 63)
• 5.1 Biotransformation and bioactivation/bioinactivation(p. 63)
• 5.2 Phase I (functionalization) and phase II (conjugation) reactions(p. 64)
• 5.2.1 Cytochrome P450 (CYP)(p. 65)
• 5.2.1.1 Mechanisms and toxicological consequences of isoform-selective CYP induction(p. 71)
• 5.2.1.2 Mechanisms and consequences of isoform-selective CYP inhibition(p. 74)
• 5.2.1.3 Bioactivation of xenobiotics by CYP(p. 76)
• 5.2.2 Peroxidases(p. 78)
• 5.2.3 UDP-glucuronosyltransferase (UGT)(p. 79)
• 5.2.3.1 Mechanisms and toxicological consequences of UGT induction(p. 82)
• 5.2.3.2 Reactive acyl glucuronides and their positional isomers(p. 82)
• 5.2.3.3 N-glucuronidation of aromatic amines(p. 83)
• 5.2.4 Sulfotransferase (SULT)(p. 86)
• 5.2.5 N-acetyltransferase (NAT)(p. 88)
• 5.2.5.1 Bioactivation of arylamines(p. 89)
• 5.2.5.2 Toxicological consequences of individual NAT expression(p. 90)
• 5.2.6 Glutathione-S-transferase (GST)(p. 93)
• 5.2.6.1 Glutathione conjugation as a protective mechanism(p. 93)
• 5.2.6.2 Bioactivation of xenobiotics by GST(p. 95)
• 5.3 Net balance of bioactivation/bioinactivation for risk assessment(p. 101)
• 5.4 Mechanisms of phototoxicity(p. 104)
• 5.5 Protective mechanisms against reactive metabolites: the stress response(p. 107)
• 5.5.1 Induction of heat-shock proteins(p. 108)
• 5.5.2 Targeting of stress-response proteins by reactive metabolites(p. 109)
• Learning points(p. 109)
• Further reading(p. 110)
• Chapter 6 Xenobiotic-Induced Oxidative Stress: Cell Injury, Signaling, and Gene Regulation(p. 117)
• 6.1 Reactive oxygen species (ROS) and oxidoreductive stress(p. 117)
• 6.1.1 Mechanisms of xenobiotic-induced intracellular ROS production(p. 119)
• 6.1.2 The key players: superoxide anion radical, hydrogen peroxide, and hydroxyl radical(p. 125)
• 6.1.3 Role of iron and other redox-active transition metals(p. 128)
• 6.1.4 Mechanisms of xenobiotic-enhanced extracellular ROS production(p. 132)
• 6.1.5 Other ROS: ozone and singlet oxygen(p. 134)
• 6.1.6 Reactive nitrogen species (RNS) and oxidative stress(p. 136)
• 6.2 Toxicological consequences of oxidative stress(p. 138)
• 6.2.1 Oxidative DNA damage(p. 139)
• 6.2.2 Oxidative protein damage(p. 142)
• 6.2.3 Oxidative lipid damage(p. 145)
• 6.3 Interference with antioxidant defense mechanisms(p. 149)
• 6.3.1 Glutathione(p. 150)
• 6.3.1.1 GSH-coupled enzyme systems(p. 151)
• 6.3.1.2 Genetic deficiency in erythrocyte glucose-6-phosphate dehydrogenase(p. 153)
• 6.3.2 Superoxide dismutase(p. 157)
• 6.3.3 Metallothionein(p. 158)
• 6.3.4 [Alpha]-Tocopherol(p. 161)
• 6.4 Intracellular signaling and gene regulation by oxidative stress(p. 161)
• Learning points(p. 169)
• Further reading(p. 169)
• Chapter 7 Disruption of Cellular Calcium Homeostasis(p. 177)
• 7.1 Xenobiotic-induced alterations in intracellular Ca[superscript 2+] distribution(p. 177)
• 7.2 Toxicological consequences of increased cytosolic Ca[superscript 2+] concentrations(p. 179)
• Learning points(p. 183)
• Further reading(p. 184)
• Chapter 8 Mechanisms of Necrotic and Apoptotic Cell Death(p. 185)
• 8.1 Necrosis(p. 185)
• 8.1.1 Mechanisms of necrosis(p. 185)
• 8.1.2 Initiation and progression of necrotic tissue injury(p. 186)
• 8.2 Apoptosis(p. 187)
• 8.2.1 Molecular mechanisms and pathways of apoptosis(p. 187)
• 8.2.1.1 Molecular mechanisms of apoptotic cell death (I)(p. 188)
• 8.2.1.2 Molecular mechanisms of apoptotic cell death (II)(p. 191)
• 8.2.2 Signaling through death receptors(p. 192)
• 8.2.3 Caspases - the executors(p. 196)
• 8.2.4 Role of mitochondria(p. 198)
• 8.2.5 Checkpoints - the Bcl-2 proteins(p. 201)
• 8.2.6 Suppression of apoptosis - toxicological consequences(p. 203)
• Learning points(p. 204)
• Further reading(p. 205)
• Chapter 9 Impairment of Cell Proliferation and Tissue Repair(p. 209)
• 9.1 The cell cycle(p. 209)
• 9.2 Stimulation of DNA synthesis and cell proliferation: xenobiotics as mitogens(p. 210)
• 9.3 Inhibition of cell proliferation by xenobiotics(p. 213)
• 9.4 Inhibition of tissue repair(p. 215)
• Learning points(p. 218)
• Further reading(p. 219)
• Chapter 10 Covalent Binding of Reactive Metabolites to Cellular Macromolecules(p. 221)
• 10.1 Electrophiles and nucleophilic targets(p. 221)
• 10.2 Covalent protein binding(p. 223)
• 10.2.1 Selectivity of covalent adduct formation(p. 224)
• 10.2.2 Downstream toxicological consequences of covalent protein binding(p. 228)
• 10.2.2.1 Covalent modification and inactivation of protein phosphatases(p. 229)
• 10.2.2.2 Covalent modification of neurofilaments(p. 233)
• 10.2.2.3 Covalent modification of proteins in the biliary tree and small intestine(p. 238)
• 10.3 Covalent DNA binding(p. 242)
• 10.3.1 Toxicological consequences of DNA alkylation(p. 243)
• Learning points(p. 245)
• Further reading(p. 246)
• Chapter 11 Immune Mechanisms(p. 251)
• 11.1 Xenobiotic-induced activation of the innate immune system(p. 252)
• 11.2 Immunosuppression by xenobiotics(p. 256)
• 11.3 Immune-mediated toxicity(p. 260)
• 11.3.1 Autoimmune reactions(p. 265)
• 11.3.2 Immunoallergy(p. 267)
• 11.3.3 Idiosyncratic reactions and the "danger" hypothesis(p. 274)
• Learning points(p. 276)
• Further reading(p. 277)
• Chapter 12 Cytokine-Mediated Toxicity(p. 281)
• 12.1 Tumor necrosis factor-[Alpha] and other proinflammatory cytokines(p. 282)
• 12.2 Chemokines and inflammatory cell recruitment(p. 285)
• Learning points(p. 287)
• Further reading(p. 288)
• Chapter 13 Specific Inactivation of Enzymes and Other Proteins(p. 289)
• 13.1 Inactivation of thiol-containing enzymes(p. 289)
• 13.2 Disruption of acetylcholinesterase activity(p. 289)
• 13.3 Transthyretin binding and inactivation: disruption of thyroid function(p. 294)
• 13.4 Inactivation of DNA-mismatch-repair proteins(p. 296)
• Learning points(p. 298)
• Further reading(p. 299)
• Chapter 14 Interactions of Xenobiotics with Ion Transporters(p. 301)
• 14.1 Interactions with neuronal Na[superscript +] channels(p. 301)
• 14.2 Interactions with the Na/K[superscript +] pump(p. 303)
• 14.3 Selective inhibition of cardiac myocyte K[superscript +] channels and QT prolongation(p. 305)
• Learning points(p. 307)
• Further reading(p. 308)
• Chapter 15 Nuclear Receptor-Mediated Toxicity(p. 309)
• 15.1 The hydrocarbon receptor (AHR)(p. 310)
• 15.1.1 AHR-mediated toxicity of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls(p. 311)
• 15.2 Xenoestrogens and antiandrogens(p. 317)
• 15.2.1 Estrogen-receptor (ER)-mediated toxicity(p. 318)
• 15.2.2 Androgen receptor (AR)-mediated toxicity(p. 321)
• 15.3 Peroxisome proliferator-activated receptors (PPARs)(p. 324)
• 15.3.1 PPAR[Alpha]-dependent toxicity(p. 326)
• 15.3.2 PPAR[gamma]-mediated toxicity(p. 328)
• 15.4 Retinoic acid receptor (RAR)(p. 332)
• Learning points(p. 334)
• Further reading(p. 335)
• Chapter 16 Activation or Disruption of Cellular Signal Transduction by Xenobiotics(p. 341)
• 16.1 Signaling: sensing and responding(p. 341)
• 16.1.1 The receptors(p. 342)
• 16.1.2 The signaling pathways(p. 343)
• 16.2 Interference with signal transduction by xenobiotics(p. 345)
• 16.2.1 Disruption of G-protein-coupled receptor function(p. 346)
• 16.2.2 Protein kinase signaling pathways(p. 347)
• 16.2.2.1 Multiple activation of protein kinase signaling pathways(p. 347)
• 16.2.2.2 Activation of protein kinase signal transduction pathways by "foreign" signaling pathways(p. 347)
• 16.2.2.3 Activation of protein kinase pathways by inactivation of phosphatases(p. 348)
• 16.2.2.4 Inactivation of selective MAPK signal transduction pathways(p. 349)
• 16.2.2.5 Activation and inactivation of JNK and its role in mitochondria-mediated cell death(p. 350)
• 16.2.3 Disruption of sensor (transcription factor) function(p. 353)
• Learning points(p. 355)
• Further reading(p. 355)
• Chapter 17 Disruption of Mitochondrial Function and Mitochondria-Mediated Toxicity(p. 357)
• 17.1 Mitochondrial targets and xenobiotic-induced bioenergy crisis(p. 357)
• 17.2 Protonophoretic and uncoupling activity of xenobiotics(p. 360)
• 17.3 Inhibition of NADH production(p. 362)
• 17.3.1 Inhibition of mitochondrial fatty acyl [Beta]-oxidation(p. 362)
• 17.3.2 Xenobiotics as pseudosubstrates for the citrate cycle(p. 365)
• 17.4 Inhibition of the electron transport chain and increased generation of ROS(p. 366)
• 17.5 Mitochondrial membrane permeabilization(p. 372)
• 17.5.1 Induction of the mitochondrial outer-membrane permeabilization (MOMP)(p. 372)
• 17.5.2 Opening of the mitochondrial membrane permeability transition (mPT) pore(p. 372)
• 17.6 Selective depletion of mitochondrial DNA(p. 377)
• Learning points(p. 380)
• Further reading(p. 381)
• Chapter 18 Novel Mechanisms Derived from Systems Toxicology(p. 385)
• Learning points(p. 389)
• Further reading(p. 389)
• Index(p. 391)