Toxicology of the Pancreas (Target Organ Toxicology Series)

The increased incidence of pancreatic cancer in the Western world and its grave prognosis has resulted in an urgency for research in this area. Until now the available data on toxicology of the pancreas has been few and fragmentary, scattered throughout the literature. A benchmark volume, Toxicology of the Pancreas pulls together information in this neglected area of toxicological research and highlights fundamental research performed in the last ten years. Leaders in the field discuss important structures, the detoxification and toxification process at the cellular and sub-cellular level, the distribution of phase 1 and phase 2 drug-metabolizing enzymes and their role in pancreatic disease, and the role of diet and toxicants on pancreatic disease. The book also covers the role of altered genes in the integrity of the pancreas and explores comparative toxicology in humans and in the lab species used in testing. Illustrated with histological, electron microscopical, and immunohistochemical formats, this book provides a comprehensive and novel presentation of biological and toxicological data. It stands alone as a reliable resource of information easily accessible to professionals in different disciplines. COVER PAGE......Page 1 TARGET ORGAN TOXICOLOGY SERIES......Page 3 TITLE PAGE......Page 6 ISBN 0415320712......Page 7 FOREWORD......Page 10 CONTRIBUTORS......Page 14 CONTENTS......Page 20 1 Developmental Biology of the Vertebrate Pancreas......Page 24 1.2 Phylogeny of Vertebrate Pancreas......Page 25 1.3 Pancreatic Organogenesis in Mammalian Models......Page 27 1.3.1.1 Early Patterning of Pancreatic Anlagen......Page 29 1.3.1.3 Endocrine Cytodifferentiation......Page 32 1.3.1.4 Exocrine Cytodifferentiation......Page 33 1.3.1.5 Regulation of Endocrine and Exocrine Differentiation......Page 35 1.3.2 Epithelial-Mesenchymal Signaling......Page 36 1.3.3 The Lineage of Endocrine Cell Types......Page 38 1.4 Pancreatic Organogenesis in Nonmammalian Models......Page 39 1.4.1 Pancreatic Development in the Zebrafish (Danio rerio, Formerly Brachydanio rerio)......Page 40 1.4.2 Pancreatic Development in Xenopus laevis......Page 45 1.4.3 Pancreatic Development in the Chick......Page 48 1.5 Pancreas Embryology in Humans......Page 49 1.6 Epilogue......Page 50 References......Page 51 2 Gross Anatomy of the Pancreas......Page 58 2.3 General Topography......Page 59 2.3.1.4 Accessory Pancreas......Page 61 2.4.1 Arteries......Page 62 2.4.3 Lymphatic Drainage......Page 63 2.4.4 Nerve Supply......Page 64 2.5.1 Anatomy......Page 65 2.5.2 Ampulla of Vater......Page 66 2.5.3 Variations of Main and Accessory Pancreatic Ducts......Page 67 2.5.4 Pancreas Divisum......Page 69 2.5.5 Termination of the Common Bile Duct and the Main Pancreatic Duct......Page 70 2.5.6 Pancreatobiliary Maljunction......Page 71 2.5.7 Choledochocele......Page 73 References......Page 75 3.1 Introduction......Page 78 3.3 General Organization of the Pancreas......Page 79 3.5 Pancreatic Acini......Page 80 3.6 Pancreatic Ducts......Page 82 3.7 Islets......Page 85 3.8 Development and Plasticity......Page 87 3.9 The Extracellular Matrix......Page 88 3.10.1 Arteries......Page 89 3.11 Lymphatics......Page 91 3.12 Nerves......Page 92 References......Page 94 4.1.1 Arterial Anatomy......Page 98 4.1.2 Venous Anatomy......Page 102 4.2.1 Lobular Vascular Bed......Page 105 4.2.2 Intralobular Islets and Their Blood Vessels......Page 107 4.2.4 Periductal Vascular Plexus......Page 110 REFERENCES......Page 111 5.1 Introduction......Page 114 5.2 What Are Centroacinar Cells?......Page 115 5.3 Topography and Fine Structure of Centroacinar Cells......Page 117 5.4 Pathology of Centroacinar Cells......Page 121 5.5 Suggested Physiological Function of Centroacinar Cells......Page 126 Acknowledgments......Page 129 References......Page 130 6 Physiology of Exocrine Pancreas......Page 132 6.1 Introduction......Page 133 6.3 Secretin......Page 134 6.4 Cholecystokinin......Page 135 6.5 Neurotensin......Page 136 6.8 Somatostatin......Page 137 6.9 Pancreatic Polypeptide......Page 138 6.10 Peptide Tyrosine Tyrosylamide......Page 139 6.12 Thyrotropin-Releasing Hormone......Page 140 6.13 Neural Regulation of Pancreatic Exocrine Secretion......Page 141 6.15 Neuropeptides and Neurotransmitters......Page 142 6.16 Nitric Oxide......Page 143 6.18 Vasoactive Intestinal Polypeptide......Page 144 6.21 Thyrotropin-Releasing Hormone......Page 145 6.22 Tachykinins......Page 146 6.25 Cocaine- and Amphetamine-Regulated Transcript Peptide......Page 147 6.26 Serotonin (5-HT)......Page 149 6.28 Feedback Regulation of Pancreatic Exocrine Secretion......Page 151 6.29 Effects of Toxic Agents to the Exocrine Pancreas......Page 156 References......Page 158 7.1 Introduction......Page 162 7.2 Phase I Metabolizing Enzymes - Cytochrome P450s......Page 164 7.3 Phase II Metabolizing Enzymes - Glutathione S-Transferases......Page 168 7.4 Miscellaneous Drug-Metabolizing Enzymes......Page 170 7.5 Problem Areas......Page 171 References......Page 178 8.2 Models for Toxicological Testing......Page 186 8.4 The Role of Islet Cells in Drug Metabolism......Page 188 8.5 Drug Metabolism in Pancreatic Diseases......Page 190 8.6 The Role of Enzymes in Pancreatic Diseases......Page 191 8.8 Epilogue......Page 192 References......Page 193 9.1 Introduction......Page 198 9.2 Pancreatic Morphogenesis......Page 199 9.2.2 Exocrine and Endocrine Cell......Page 201 9.4 Regulation of Pancreatic Secretion......Page 204 9.5 Clinical Implications of Exocrine and Endocrine Interactions......Page 208 References......Page 209 10 Nutritional Requirements of the Pancreas......Page 214 10.2.1 Protein Energy Malnutrition......Page 215 10.2.1.2 The Pancreas in Kwashiorkor......Page 216 10.2.1.3 Tropical (Nutritional) Pancreatitis......Page 217 10.2.2 Methyl Deficiency......Page 218 10.2.3 Choline Deficiency......Page 219 10.2.4.2 Copper......Page 220 10.2.5.1 Folate Deficiency......Page 221 10.2.6.2 Trypsin Inhibitors......Page 222 10.2.6.3 High-Fat Diets......Page 223 10.4 Epilogue......Page 224 References......Page 225 11.1 Introduction......Page 230 11.2 Mutational Analysis of PSTI Gene in Familial and Juvenile Pancreatitis in Japan......Page 231 11.3 Generation and Analysis of PSTI Knockout Mice......Page 233 11.4 Functional Analysis of Recombinant PSTI Proteins with Amino Acid Substitution......Page 235 11.5 Epilogue......Page 237 References......Page 238 12.1 Introduction......Page 240 12.2 Structure and Classification of Mucins......Page 241 12.2.2 Membrane-Bound Mucins......Page 244 12.3 Mucin Biosynthesis......Page 245 12.4 Expression Profiles of Human Mucins in the Pancreas......Page 246 12.5 Abnormal Glycosylation of Mucins in Pancreatic Cancer......Page 249 12.6 Functional Aspects of Mucins and Pathophysiological Implications......Page 251 12.7 Mucins in Diagnosis and Therapy......Page 253 12.8 Epilogue......Page 255 References......Page 256 13 Growth Factors in Pancreatic Diseases......Page 266 13.1 Introduction......Page 267 13.2 Insulin in Pancreatic Diseases......Page 268 13.2.1 Insulin in the Normal Pancreas......Page 269 13.2.2 Insulin in AP......Page 270 13.2.3 Insulin in CP......Page 271 13.3 The Insulin-like Growth Factor and Its Receptor in Pancreatic Diseases......Page 272 13.3.2 IGF in PC......Page 273 13.4 The Transforming Growth Factor b Family in Pancreatic Diseases......Page 274 13.4.1 The TGF-b Family in AP......Page 275 13.4.3 The TGF-b Family in PC......Page 276 13.5 The EGF Receptor Family and Its Ligands in Pancreatic Diseases......Page 279 13.5.2 The EGF Receptor Family and Its Ligands in AP......Page 280 13.5.3 The EGF Receptor Family and Its Ligands in CP......Page 281 13.5.4 The EGF Receptor Family and Its Ligands in PC......Page 282 13.6.1 HGF and MET in AP......Page 284 13.7 The Fibroblast Growth Factor Receptors and Their Ligands in Pancreatic Diseases......Page 285 13.7.2 FGFs and Receptors in AP......Page 286 13.7.4 FGFs and Receptors in PC......Page 287 13.8.1 NTs in AP......Page 289 13.8.2 NTs in CP......Page 290 13.8.3 NTs in PC......Page 292 References......Page 293 14 Toxicology of Natural Hormones and Hormonelike Chemicals......Page 306 14.2.1.1 CCK and CCK Receptors......Page 307 14.2.3 Acetylcholine-Mediated Acinar Cell Secretion......Page 309 14.2.5 The CCK Feedback Loop......Page 310 14.2.6 Protein Synthesis, Transport, and Secretion......Page 312 14.3 CCK-Induced Pancreatitis......Page 313 14.3.2 Evolution of Cerulein-Induced Pancreatitis......Page 314 14.3.4 Acinar Cell Events during Cerulein-Induced Pancreatitis......Page 316 14.3.4.1 Events Related to Acinar Cell Injury......Page 318 14.3.4.3 Sequence of Acinar Cell Events......Page 320 14.3.5.1 Acetylcholine......Page 323 14.4 Hormone-Induced Growth and Neoplasia......Page 324 14.5 Epilogue......Page 325 References......Page 326 15 Alcohol and Pancreatitis......Page 330 15.2 Epidemiology of Alcoholic Chronic Pancreatitis......Page 331 15.3 Natural Course of Alcoholic Chronic Pancreatitis......Page 332 15.4.1 Alcohol and Pancreatic Exocrine Secretion......Page 334 15.4.1.1 Effects of Acute Ethanol Administration In Vivo......Page 335 15.4.1.2 Effects of Acute Ethanol Administration In Vitro......Page 336 15.4.1.3 Effects of Acute Administration of Alcoholic Beverages......Page 337 15.4.3 Metabolism of Alcohol in the Pancreas......Page 338 15.4.3.2 Nonoxidative Pathway......Page 339 15.4.4 Alcohol and Oxidative Stress......Page 340 15.4.6 Alcoholic Pancreatitis and Nutrition......Page 341 15.4.7 Alcohol and Pancreatic Stellate Cells......Page 342 15.5 Epilogue......Page 343 References......Page 344 16.1 Introduction......Page 352 16.2 Type of Pancreatitis, Initial Damage in the Pancreas, and Fibrosis Pattern......Page 354 16.2.1 Alcoholic Chronic Pancreatitis......Page 355 16.2.2 Hereditary Chronic Pancreatitis......Page 357 16.2.3 Autoimmune (Duct Destructive) Chronic Pancreatitis......Page 358 16.2.5 Obstructive Chronic Pancreatitis......Page 360 16.3 Conclusion......Page 362 References......Page 363 17.1 Introduction......Page 366 17.2 Pancreatic Injury by DLCs......Page 368 References......Page 374 18 Chronic Pancreatic Toxicity - Role of Stem Cells in the Conversion of Pancreas to Liver......Page 378 18.1 Introduction......Page 379 18.1.2 Lineage Switches of Cells - Definitions......Page 380 18.2.1 Hamster Model......Page 381 18.2.3.1 Ciprofibrate Model......Page 382 18.2.3.6 Copper-Deficiency Model......Page 383 18.3.1 Ductular and Oval Cells as the Progenitor Cells of Pancreatic Hepatocytes......Page 391 18.3.2 Differentiation Potential of Oval and Ductular Cells - In Vitro and In Vivo Studies......Page 392 18.4 Possible Mechanisms Involved in the Induction of Pancreatic Hepatocytes......Page 393 REFERENCES......Page 394 19 Environmental Factors and Exocrine Pancreatic Disease......Page 402 19.2.1 Biliary Pancreatitis......Page 403 19.2.3 Miscellaneous Causes of Acute Pancreatitis......Page 404 19.3.1 Alcohol and Chronic Pancreatitis......Page 405 19.3.2 Smoking and Chronic Pancreatitis......Page 406 19.3.5 Hereditary Pancreatitis......Page 407 19.4 Pancreas Cancer......Page 408 19.4.1 Tobacco Carcinogens and Pancreatic Cancer......Page 410 19.4.2 Diet and Pancreatic Cancer......Page 411 19.5 Epilogue......Page 412 References......Page 414 20 Environmental Determinants of Exocrine Pancreatic Cancer......Page 418 20.1 Introduction......Page 419 20.3 Dietary Factors......Page 420 20.3.1 Fat......Page 421 20.3.2 Carbohydrates and Insulin Resistance......Page 422 20.3.3 Vegetables and Fruits......Page 423 20.3.4 Alcohol......Page 424 20.4 Obesity......Page 425 20.5 Physical Activity......Page 426 20.6 Exogenous Sex Hormones......Page 427 20.7 Helicobacter Pylori Infection......Page 428 20.8 NSAIDS......Page 429 20.10 Pesticides......Page 430 20.11.1 Carcinogen Metabolism, Oxidative Stress......Page 432 20.11.2 Inflammation......Page 433 20.11.3 DNA Repair......Page 434 20.11.4 Hormonal Pathways......Page 435 20.12 Epilogue......Page 436 References......Page 437 21.1 Introduction......Page 446 21.2 The Effects of Diet on Survival......Page 447 21.4 Mechanism of the Effect of Diet on Carcinogenesis......Page 448 21.5 Nutrients as Preventive Agents......Page 449 21.7 Epilogue......Page 450 References......Page 451 22.1 Introduction......Page 456 22.2 Animal Bioassays - Agents that Induce Pancreatic Cancer in Laboratory Animals......Page 457 22.3.1 Tobacco Components......Page 463 22.3.2 Metabolic Activation and DNA Adducts......Page 464 22.4 Modifiers of N-Nitrosamine Carcinogenesis......Page 468 22.5 Genetic Alteration in Pancreatic Cancer and Potential Biomarkers......Page 469 22.6 Epilogue......Page 470 References......Page 471 23.1 Introduction......Page 482 23.2 Definition and Concept of AIP......Page 483 23.4 Associating Diseases......Page 484 23.6 Laboratory Data......Page 485 23.7 Pancreatic Imaging......Page 486 23.8 Histopathology......Page 487 23.9 Diagnosis and Differential Diagnosis of AIP......Page 488 23.10 Treatment and Prognosis......Page 489 23.11.1 Humoral Immunity and Target Antigens......Page 491 23.11.3 Experimental Autoimmune Pancreatitis Using Animal Models......Page 492 Acknowledgments......Page 493 References......Page 494 24.1 Introduction......Page 498 24.2 Susceptibility to Environmental Toxins......Page 499 24.3 Metabolic Disorders......Page 500 24.4 Hereditary Pancreatitis......Page 501 24.5 Cationic Trypsinogen......Page 502 24.6 Anionic Trypsinogen and Mesotrypsinogen......Page 504 24.7 The Pancreatic Secretory Trypsin Inhibitor Gene (SPINK-1)......Page 506 24.9 Polymorphism in Genes of the Inflammatory Response System......Page 508 24.10 Genetic Predisposition in Alcoholic Pancreatitis......Page 509 References......Page 510 25 Genetic Disorders Associated with Exocrine and Endocrine Pancreatic Tumors......Page 514 25.2 Epidemiology......Page 515 25.4 Case-Control Studies of Familial Risk Factors......Page 516 25.5 Pancreatic Cancer - An Important Medical and Genetic Model......Page 517 25.8 PJS and PC......Page 518 25.9 FAMMM Syndrome and PC......Page 519 25.10 BRCA2 Mutations in Familial Pancreatic Cancer......Page 523 25.12 Pancreatic Endocrine Tumors......Page 527 25.13.1 Multiple Endocrine Neoplasia Type 1 (MEN 1)......Page 528 25.13.3 VHL Disease......Page 530 25.15 Epilogue......Page 531 25.15.1 Knowledge Gleaned from Study of Genetics of Breast and Colon Cancer and Their Influence on PC......Page 532 Acknowledgments......Page 533 References......Page 534 26 Cystic Fibrosis of the Pancreas - the Disease and Its Manifestations......Page 542 26.2 Molecular Basis of CF......Page 543 26.4 Pathological Alterations in the Pancreas......Page 546 26.5 Pathophysiology......Page 548 26.6.1 Pancreatic Insufficiency......Page 549 26.6.2 CF-Related Diabetes......Page 552 26.6.3 Pancreatitis......Page 553 26.7 Diagnosis......Page 554 26.7.4.1 Blood Biochemistry......Page 555 26.8 CF and Pancreatic Cancer......Page 556 26.9 Epilogue......Page 558 References......Page 559 27.1 Introduction......Page 564 27.2.1 Diabetogenic Action of STZ......Page 565 27.2.2 The Mechanisms of Streptozotocin Action......Page 566 27.2.3 Species Differences of STZ Action......Page 568 27.2.4 Tumorigenic Action of STZ......Page 571 27.2.5 Antitumor Action of STZ......Page 573 27.3 Alloxan......Page 574 27.3.1 The Mechanisms of Alloxan Action......Page 577 27.3.2 Species Differences with Alloxan Action......Page 581 27.3.4 Antitumor Action of Alloxan......Page 582 27.5 Endogenous Substances Toxic to Pancreatic b-Cells......Page 584 References......Page 586 28 Alterations of the Endocrine Pancreas......Page 602 28.2.1 Cell Types......Page 603 28.2.3 Vasculature......Page 606 28.2.5 Hormone Signaling and Regulation......Page 607 28.3 Islet Development......Page 608 28.3.1 Genetic Regulation......Page 609 28.4 Islet Maintenance......Page 612 28.4.1 Animal Models of Neogenesis......Page 613 28.5 Effects of Isolation and Transplantation on Islet Viability and Survival......Page 615 28.7 Insults of Isolation on Islets......Page 617 28.9 Cell Death Mechanisms......Page 618 28.9.1 Possible Causes of Isolated Islet Apoptosis......Page 620 28.10 Signaling Events Following Isolation......Page 623 28.10.2 JNK......Page 624 28.10.3 P38......Page 625 28.10.4 ERK......Page 626 28.10.5 AKT......Page 627 28.10.7 Bcl-2 Proteins......Page 628 28.11.1 Therapeutic Opportunities......Page 629 28.11.3 Growth Factors......Page 630 28.11.4 Nicotinamide......Page 632 28.11.6 JNK Inhibition......Page 633 28.11.9 Gene Therapy......Page 634 28.12 Islet Phenotypic Stability following Isolation......Page 635 28.12.1.1 Growth Factors/Signaling......Page 636 28.12.3.1 Support for Islet-to-Duct-to-Cancer Paradigm......Page 638 28.13 Epilogue......Page 639 References......Page 641 29 Pancreatic Cancer and Diabetes - Cellular Origin of Adeonocarcinoma......Page 668 29.2 Anatomy of the Pancreas......Page 669 29.3.1 Adenocarcinomas of the Pancreas......Page 671 29.3.2 Familial Pancreatic Cancer......Page 675 29.3.3 Endocrine Cancer of the Pancreas......Page 676 29.4 Diabetes Mellitus and Pancreatic Cancer......Page 677 29.5 Diabetes: Cause or Effect of Pancreatic Cancer......Page 680 29.6 Origin of Pancreatic Adenocarcinoma......Page 681 29.7 Transdifferentiation of Pancreatic Cells......Page 683 29.8 Conclusions and Perspectives......Page 684 References......Page 685 A......Page 694 B......Page 697 C......Page 698 D......Page 702 F......Page 704 G......Page 705 I......Page 707 L......Page 709 M......Page 710 O......Page 711 P......Page 712 S......Page 715 T......Page 716 Z......Page 718

the Increased Incidence Of Pancreatic Cancer In The Western World And Its Grave Prognosis Has Resulted In An Urgency For Research In This Area. Until Now The Available Data On Toxicology Of The Pancreas Has Been Few And Fragmentary, Scattered Throughout The Literature. A Benchmark Volume, Toxicology Of The Pancreas Pulls Together Information In This Neglected Area Of Toxicological Research And Highlights Fundamental Research Performed In The Last Ten Years.

leaders In The Field Discuss Important Structures, The Detoxification And Toxification Process At The Cellular And Sub-cellular Level, The Distribution Of Phase 1 And Phase 2 Drug-metabolizing Enzymes And Their Role In Pancreatic Disease, And The Role Of Diet And Toxicants On Pancreatic Disease. The Book Also Covers The Role Of Altered Genes In The Integrity Of The Pancreas And Explores Comparative Toxicology In Humans And In The Lab Species Used In Testing.

illustrated With Histological, Electron Microscopical, And Immunohistochemical Formats, This Book Provides A Comprehensive And Novel Presentation Of Biological And Toxicological Data. It Stands Alone As A Reliable Resource Of Information Easily Accessible To Professionals In Different Disciplines.

A benchmark volume, Toxicology of the Pancreas pulls together information in this neglected area of toxicological research and highlights fundamental research performed in the last 10 years. Leaders in the field discuss important structures, the detoxification and toxification process at the cellular and sub-cellular level, the distribution of phase 1 and phase 2 drug-metabolizing enzymes and their role in pancreatic disease, and the role of diet and toxicants on pancreatic disease.The book also covers the role of altered genes in the integrity of the pancreas and explores comparative toxicology in humans and in the lab species used in testing. Illustrated with histological, electron microscopical, and immunohistochemical formats, it provides a comprehensive and novel presentation of biological and toxicological data. The book stands alone as a reliable resource of information easily accessible to professionals in different disciplines.