Parviz M. Pour0415320712, 9780415320719
Table of contents :
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
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