Bile Acids: Toxicology and Bioactivity

175 Pages·2008·1.97 MB·English

by  Gareth J Jenkins

Bile Acids
Toxicology and Bioactivity
Issues in Toxicology
Series Editors
ProfessorDianaAnderson,UniversityofBradford,UK
DrMichaelDWaters,NationalInstituteofEnvironmentalHealthScience,
NCarolina,USA
DrTimothyCMarrs,EdentoxAssociates,Kent,UK
ThisSeries is devoted to coverage of modern toxicologyand assessment of risk andis
respondingtotheresurgenceininterestintheseareasofscientificinvestigation.
Ideal as a reference and guide to investigations in the biomedical, biochemical and
pharmaceuticalsciencesatthegraduateandpostgraduatelevel.
Titles in the Series:
BileAcids:ToxicologyandBioactivity
Edited by Gareth Jenkins, Institute of Life Science, Swansea School of Medicine,
SwanseaUniversity,Swansea,UKandLauraJ.Hardie,MolecularEpidemiologyUnit,
UniversityofLeeds,Leeds,UK
CytochromeP450:RoleintheMetabolismandToxicityofDrugsandotherXenobiotics
EditedbyCostasIoannides,UniversityofSurrey,Guildford,UK
HairinToxicology:AnImportantBio-Monitor
EditedbyDesmondJohnTobin,UniversityofBradford,Bradford,UK
Male-mediatedDevelopmentalToxicity
EditedbyDianaAndersonandMartinHBrinkworth,UniversityofBradford,
Bradford,UK
Visitourwebsiteatwww.rsc.org/issuesintoxicology
Forfurtherinformationpleasecontact:
SalesandCustomerCare,RoyalSocietyofChemistry,ThomasGrahamHouse,
SciencePark,MiltonRoad,Cambridge,CB40WF,UK
Telephoneþ44(0)1223432360,Fax:þ44(0)1223426017,Email:[email protected]
Bile Acids
Toxicology and Bioactivity
Edited by
Gareth Jenkins
Institute of Life Science, Swansea School of Medicine, Swansea University,
Swansea, UK
Laura J. Hardie
Molecular Epidemiology Unit, University of Leeds, Leeds, UK
ISBN: 978-0-85404-846-5
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
rRoyalSocietyofChemistry,2008
Allrightsreserved
Apart from fair dealing for the purposes of research for noncommercial purposes or for
privatestudy,criticismorreview,aspermittedundertheCopyright,DesignsandPatents
Act1988andtheCopyrightandRelatedRightsRegulations2003,thispublicationmaynot
be reproduced, stored or transmitted, in any form or by any means, without the prior
permissioninwritingofTheRoyalSocietyofChemistryorthecopyrightowner,orinthe
case of reproduction in accordance with the terms of licences issued by the Copyright
LicensingAgencyintheUK,orinaccordancewiththetermsofthelicencesissuedbythe
appropriate Reproduction Rights Organization outside the UK. Enquiries concerning
reproduction outside the terms stated here should be sent to The Royal Society of
Chemistryattheaddressprintedonthispage.
PublishedbyTheRoyalSocietyofChemistry,
ThomasGrahamHouse,SciencePark,MiltonRoad,
CambridgeCB40WF,UK
RegisteredCharityNumber207890
Forfurtherinformationseeourwebsiteatwww.rsc.org
Preface
We present here a full and detailed set of reviews focusing on the toxicology
and bioactivity of bile acids. We have brought together world experts in their
own fields to discuss the contribution of bile acids to various disease patho-
logies, as well as discussing the mechanisms behind their activity.
Thisexciting manuscript,forthefirsttime,details theplethoraofbiological
activities of this fascinating group of naturally occurring chemicals. We hope
that this provides a one-stop reference for scientists to gain a fuller under-
standing of bile-acid activity and function.
Bile acids are essential agents involved in lipid digestion and absorption in
mammals.However, they playwide-rangingroles in avarietyof disease states
ranging from diabetes to cancer. They have evolved exquisite mechanisms for
controllingtheirownsynthesisandtoensurethattheyareproducedatcorrect
concentrations and also keptin thecorrect anatomical environment. Itisonly
whenthesefinelevelsofcontrolsarebreachedthatbileacidsbecomeassociated
withdisease.Thisbreachingofcontrolmechanismscan occurthrough dietary
means (e.g. in obesity) whereby excessive levels of bile acids are produced and
converted (via the bacterial flora) to damaging secondary bile acids. Further-
more, lack of reabsorption of Bile acids can lead to liver pathologies. The
atypicalmovementofBileacidsintotheoesophagus,stimulatedbyepisodesof
reflux, is linked to oesophageal cancer.
Wewouldliketothankeveryonewhohascontributedtothisbookandhope
that the readers of this manuscript find the text stimulating and rewarding in
terms of their understanding of the mechanisms underlying bile-acid induced
pathology.
Gareth Jenkins and Laura J. Hardie
IssuesinToxicology
BileAcids:ToxicologyandBioactivity
EditedbyGarethJenkinsandLauraJ.Hardie
rRoyalSocietyofChemistry,2008
v
vi Preface
‘‘By the gods, you can swallow your own bile till it kills you’’
William Shakespeare
Brutus to Cassius in Julius Caesar
In Shakespeare’s time, the traditional model of illness was as an imbalance of
the four humours: melancholy (or black bile), choler (or yellow bile), blood,
and phlegm.
Contents
Chapter 1 An Overview of Bile-Acid Synthesis, Chemistry
and Function
Dennis Stamp and Gareth Jenkins
1.1 The Bile Acids 1
1.2 Conjugated Bile-Acid Biosynthesis 4
1.3 Bile-Acid Regulation 4
1.3.1 Bile-Acid Receptors (FXR) 4
1.3.2 Cholesterol Receptors (LXR) (NR1H3)
and (NR1H2) 5
1.4 Chemistry of Bile Acids and Their Effects
on Digestion 6
1.5 Micelles 7
1.6 BiochemicalPropertiesofBileAcidsandTheirEffects
on the GI Tract 8
1.6.1 Free Bile Acids 9
1.6.2 Glycine-Conjugated BAs 9
1.6.3 Taurine Conjugated dBAs 9
1.7 The Effect of pH on Bile-Acid Solubility 9
1.8 Potential Therapies for the Deleterious Effects
of Bile Acids 10
1.9 Summary 11
References 11
Chapter 2 Bile-Acid Physiology and Measurement
Peter E. Ross
2.1 Bile-Acid Physiology: The Enterohepatic Circulation 14
2.2 Transport in Blood 15
IssuesinToxicology
BileAcids:ToxicologyandBioactivity
EditedbyGarethJenkinsandLauraJ.Hardie
rRoyalSocietyofChemistry,2008
vii
viii Contents
2.3 The Hepatocyte 15
2.4 SodiumTaurocholateCo-transportingProtein(NTCP) 16
2.5 Organic-Anion-Transporting Peptide (OATP) 17
2.6 Specificity of OATP and NTCP Transporters 17
2.7 Regulation of Expression 19
2.8 Transport across the Hepatocyte 20
2.9 Bile-Acid Export from the Hepatocyte 21
2.9.1 Bile-Salt Export Pump (BSEP) 21
2.9.2 Regulation of BSEP 22
2.9.3 Other Transporters that Export Bile Acid
from the Hepatocyte 25
2.10 Bile Secretion 25
2.11 Water Secretion 27
2.12 Cholangiocytes 27
2.13 Cholangiocyte Secretion 28
2.14 Gallbladder 29
2.15 Small Bowel 30
2.16 Intestinal Fat Absorption 30
2.17 Bile-Acid Absorption 30
2.17.1 Apical Sodium-Dependent Bile-Acid
Transporter (ASBT) 31
2.17.2 Regulation 32
2.17.3 Post-Translational Modification 33
2.18 Transport across the Enterocyte 33
2.19 Export into Portal Blood 34
2.20 Colon 35
2.20.1 Deconjugation 35
2.20.2 Oxidation of Hydroxyl Groups 35
2.20.3 Dehydroxylation 35
2.21 Measurement of Bile Acids 36
2.21.1 Extraction 36
2.21.2 Hydroxysteroid Dehydrogenases 37
2.21.3 Chromatographic Assays 37
2.21.3.1 Gas-Liquid Chromatography (glc) 37
2.21.3.2 High-Performance Liquid
Chromatography (hplc) 38
2.21.4 Radioimmunoassay 38
Abbreviations 38
References 39
Chapter 3 Bile-Acid Induction of Apoptosis in Relation to
Gastrointestinal Cancer
Katerina Dvorak, Harris Bernstein, Claire M. Payne,
Carol Bernstein and Harinder Garewal
3.1 Introduction 48
Contents ix
3.2 Bile Acids Induce Oxidative/Nitrosative Stress
in Cells of the GI Tract 51
3.3 Bile Acids Induce DNA Damage in Cells
of the GI Tract 54
3.4 Bile Acids Activate NF-kB as a Stress Response and
Survival Pathway Throughout the GI Tract 54
3.5 Bile Acids Increase Mutant Cells in the GI Tract 55
3.6 Repeated Exposure to High Concentrations of Bile
Acids Probably Selects for Apoptosis Resistance in
Cells of the GI Tract 56
3.7 Apoptosis Resistance and Increased Mutation 58
3.8 Modes of Cell Death: Apoptosis, Autophagy
and Necrosis 59
3.9 Overview 60
Acknowledgments 61
References 61
Chapter 4 The Genotoxicity of Bile Acids
Laura J. Hardie
4.1 Introduction 72
4.2 Definitions 72
4.3 Bile Acids as Carcinogens 73
4.4 DNA Adducts 74
4.5 Bile Acids cause DNA Damage 74
4.6 The Role of Reactive Oxygen and Nitrogen Species 76
4.7 Mutagenic Effects of Bile Acids 77
4.8 Bile Acids and Chromosomal Damage 79
4.9 Chemoprevention Strategies 80
4.10 Summary and Concluding Remarks 80
References 81
Chapter 5 Bile Acids and Colorectal Cancer
Mark A. Hull
5.1 Introduction 84
5.2 Multi-stage Colorectal Carcinogenesis 84
5.3 Evidence that Bile Acids Play a Role
in Colorectal Carcinogenesis 86
5.3.1 ActivityofBileAcidsinRodentModelsofCRC 86
5.3.2 Human Observational Data 86
5.4 Mechanisms of the Carcinogenic Activity
of Secondary Bile Acids 89
5.5 Colorectal Cancer Chemoprevention Strategies
Targeting Bile Acids 90
x Contents
5.5.1 Ursodeoxycholic Acid 90
5.5.2 Other Agents Targeting Mucosal Bile Acid
Exposure 92
5.5.3 Therapeutic Anti-cancer Use of Bile Acid
Conjugates 93
5.6 Summary 93
Acknowledgement 93
References 94
Chapter 6 Bile Acids and Oesophageal Adenocarcinoma (OA)
Gareth Jenkins and James Cronin
6.1 Oesophageal Adenocarcinoma 100
6.2 Oesophageal Bile Acid Exposure 101
6.3 Bile Acids and Diet 103
6.4 Duodeno-Gastro-Oesophageal Reflux (DGOR);
Animal Models 103
6.5 Duodeno-Gastro-Oesophageal Reflux (DGOR);
Clinical Data 105
6.6 Measurement of Bile in the Oesophagus 109
6.7 Mechanisms behind the Carcinogenicity
of Bile Acids 110
6.8 The Interplay between Acid and Bile in GORD 112
6.9 Deconjugation of Bile Acids in Nonacidic
Stomach 112
6.10 Effect of Acidity on Bile Acid Solubility 113
6.11 Acid-Suppression Therapy and Risks of OA 114
6.12 Bile Acid Therapy 115
6.13 Conclusions 115
Acknowledgements 116
References 116
Chapter 7 Bile Acids and Obesity
Lucinda Summers and Laura J. Hardie
7.1 Obesity 122
7.1.1 Epidemiology 123
7.1.2 Morbidity and Mortality 124
7.2 Adipose Tissue 124
7.2.1 Regulation of Fatty Acid and Glucose
Metabolism in Adipocytes 125
7.2.2 Adipose Tissue as an Endocrine Organ 126
7.3 Common Complications of Obesity 127
7.3.1 Insulin Resistance 127
7.3.2 Impaired Glucose Tolerance 129
7.3.3 Dyslipidemia 129