Bile Acids

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ISBN: 9780854048465 | 0854048464
Cover: Hardcover
Copyright: 11/1/2008

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"Bile acids are increasingly being seen as extremely important carcinogenic agents in cancers of the bile duct, liver, colon, rectum, and oesophagus. In recent years there have been tremendous advances in the understanding of the mechanisms behind the toxicity and bioactivity of different bile acids and these are covered at length in this book." "Prior to the publication of Bile Acids: Toxicology and Bioactivity there was no single source of information on the toxicology and bioactivity of bile acids. This unique book collects all the relevant information together regarding the role of bile acids in human disease. In addition to their role in cancer development and gallstone formation, this book highlights recent evidence linking bile acids to obesity related diseases." "The book also includes contributions by experts in the field and will appeal to all researchers who wish to understand bile acid toxicology and bioactivity and its role in human disease."--BOOK JACKET.

An Overview of Bile-Acid Synthesis, Chemistry and Function
The Bile Acids	p. 1
Conjugated Bile-Acid Biosynthesis	p. 4
Bile-Acid Regulation	p. 4
Bile-Acid Receptors (FXR)	p. 4
Cholesterol Receptors (LXR) (NR1H3) and (NR1H2)	p. 5
Chemistry of Bile Acids and Their Effects on Digestion	p. 6
Micelles	p. 7
Biochemical Properties of Bile Acids and Their Effects on the GI Tract	p. 8
Free Bile Acids	p. 9
Glycine-Conjugated BAs	p. 9
Taurine Conjugated dBAs	p. 9
The Effect of pH on Bile-Acid Solubility	p. 9
Potential Therapies for the Deleterious Effects of Bile Acids	p. 10
Summary	p. 11
References	p. 11
Bile-Acid Physiology and Measurement
Bile-Acid Physiology: The Enterohepatic Circulation	p. 14
Transport in Blood	p. 15
The Hepatocyte	p. 15
Sodium Taurocholate Co-transporting Protein (NTCP)	p. 16
Organic-Anion-Transporting Peptide (OATP)	p. 17
Specificity of OATP and NTCP Transporters	p. 17
Regulation of Expression	p. 19
Transport across the Hepatocyte	p. 20
Bile-Acid Export from the Hepatocyte	p. 21
Bile-Salt Export Pump (BSEP)	p. 21
Regulation of BSEP	p. 22
Other Transporters that Export Bile Acid from the Hepatocyte	p. 25
Bile Secretion	p. 25
Water Secretion	p. 27
Cholangiocytes	p. 27
Cholangiocyte Secretion	p. 28
Gallbladder	p. 29
Small Bowel	p. 30
Intestinal Fat Absorption	p. 30
Bile-Acid Absorption	p. 30
Apical Sodium-Dependent Bile-Acid Transporter (ASBT)	p. 31
Regulation	p. 32
Post-Translational Modification	p. 33
Transport across the Enterocyte	p. 33
Export into Portal Blood	p. 34
Colon	p. 35
Deconjugation	p. 35
Oxidation of Hydroxyl Groups	p. 35
Dehydroxylation	p. 35
Measurement of Bile Acids	p. 36
Extraction	p. 36
Hydroxysteroid Dehydrogenases	p. 37
Chromatographic Assays	p. 37
Gas-Liquid Chromatography (glc)	p. 37
High-Performance Liquid Chromatography (hplc)	p. 38
Radioimmunoassay	p. 38
Abbreviations	p. 38
References	p. 39
Bile-Acid Induction of Apoptosis in Relation to Gastrointestinal Cancer
Introduction	p. 48
Bile Acids Induce Oxidative/Nitrosative Stress in Cells of the GI Tract	p. 51
Bile Acids Induce DNA Damage in Cells of the GI Tract	p. 54
Bile Acids Activate NF-[kappa]B as a Stress Response and Survival Pathway Throughout the GI Tract	p. 54
Bile Acids Increase Mutant Cells in the GI Tract	p. 55
Repeated Exposure to High Concentrations of Bile Acids Probably Selects for Apoptosis Resistance in Cells of the GI Tract	p. 56
Apoptosis Resistance and Increased Mutation	p. 58
Modes of Cell Death: Apoptosis, Autophagy and Necrosis	p. 59
Overview	p. 60
Acknowledgments	p. 61
References	p. 61
The Genotoxicity of Bile Acids
Introduction	p. 72
Definitions	p. 72
Bile Acids as Carcinogens	p. 73
DNA Adducts	p. 74
Bile Acids cause DNA Damage	p. 74
The Role of Reactive Oxygen and Nitrogen Species	p. 76
Mutagenic Effects of Bile Acids	p. 77
Bile Acids and Chromosomal Damage	p. 79
Chemoprevention Strategies	p. 80
Summary and Concluding Remarks	p. 80
References	p. 81
Bile Acids and Colorectal Cancer
Introduction	p. 84
Multi-stage Colorectal Carcinogenesis	p. 84
Evidence that Bile Acids Play a Role in Colorectal Carcinogenesis	p. 86
Activity of Bile Acids in Rodent Models of CRC	p. 86
Human Observational Data	p. 86
Mechanisms of the Carcinogenic Activity of Secondary Bile Acids	p. 89
Colorectal Cancer Chemoprevention Strategies Targeting Bile Acids	p. 90
Ursodeoxycholic Acid	p. 9
Other Agents Targeting Mucosal Bile Acid Exposure	p. 92
Therapeutic Anti-cancer Use of Bile Acid Conjugates	p. 93
Summary	p. 93
Acknowledgement	p. 93
References	p. 94
Bile Acids and Oesophageal Adenocarcinoma (OA)
Oesophageal Adenocarcinoma	p. 100
Oesophageal Bile Acid Exposure	p. 101
Bile Acids and Diet	p. 103
Duodeno-Gastro-Oesophageal Reflux (DGOR); Animal Models	p. 103
Duodeno-Gastro-Oesophageal Reflux (DGOR); Clinical Data	p. 105
Measurement of Bile in the Oesophagus	p. 109
Mechanisms behind the Carcinogenicity of Bile Acids	p. 110
The Interplay between Acid and Bile in GORD	p. 112
Deconjugation of Bile Acids in Nonacidic Stomach	p. 112
Effect of Acidity on Bile Acid Solubility	p. 113
Acid-Suppression Therapy and Risks of OA	p. 114
Bile Acid Therapy	p. 115
Conclusions	p. 115
Acknowledgements	p. 116
References	p. 116
Bile Acids and Obesity
Obesity	p. 122
Epidemiology	p. 123
Morbidity and Mortality	p. 124
Adipose Tissue	p. 124
Regulation of Fatty Acid and Glucose Metabolism in Adipocytes	p. 125
Adipose Tissue as an Endocrine Organ	p. 126
Common Complications of Obesity	p. 127
Insulin Resistance	p. 127
Impaired Glucose Tolerance	p. 129
Dyslipidemia	p. 129
Effect of Bile Acids on Obesity	p. 130
Bile Acids, the Farnesoid X Receptor (FXR) and Fat Metabolism	p. 132
Bile-Acid Sequestrants	p. 133
Chemical Composition of BAS	p. 134
Effect of Bile-Acid Sequestrants on Type-2 Diabetes and Obesity	p. 134
Summary	p. 137
References	p. 137
The Role of Bile Acids in Cholesterol-Rich Gallstone Formation
Introduction	p. 141
The Triple Defect of Cholesterol GBS Formation	p. 142
Vesicles versus Micelles	p. 143
Nucleation of Cholesterol Crystals	p. 143
Promoters and Inhibitors of Nucleation	p. 144
Stasis	p. 144
Indirect Evidence that Gallbladder Motor Dysfunction/Stasis is Important in the Pathogenesis of GBS	p. 145
The Octreotide Story	p. 145
Biliary Phospholipid Fatty-Acid Composition	p. 148
Biliary Bile-Acid Composition	p. 149
The Adverse Effects of Increased Proportions of DCA in Bile on Cholesterol Gallstone Formation	p. 149
Mechanism for the Increase in the % Biliary DCA Conjugates in Bile during Octreotide Treatment	p. 151
The Relationship between Colonic Transit and DCA Metabolism	p. 151
The Role of Prolonged Intestinal Transit in the Pathogenesis of Conventional Cholesterol Gallstones	p. 151
The Inter-Relationship between LBTT, Colonic Anaerobic Bacteriology, Bile-Acid-Metabolising Enzymes, Intraluminal pH and DCA Metabolism	p. 152
Summary	p. 156
References	p. 156
Subject Index	p. 159
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