Chemopräventive Effekte von n-3 mehrfach ungesättigten Fettsäuren und Fisch in humanen Kolonzellen [Elektronische Ressource] = Chemopreventive effects of n-3 polyunsaturated fatty acids and fish in human colon cells / von Nina Habermann

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• Gesundheit

Informations

• Publié par: friedrich-schiller-universitat_jena
• Publié le: 01 janvier 2010
• Nombre de lectures: 25
• Langue: English
• Poids de l'ouvrage: 9 Mo

Extrait

Chemopräventive Effekte von n-3 mehrfach ungesättigten
Fettsäuren und Fisch in humanen Kolonzellen










Dissertation
zur Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer. nat.)

vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät
der Friedrich-Schiller-Universität Jena



von
Dipl. troph. Nina Habermann
geboren am 31. August 1979
in Eisenach Chemopreventive effects of n-3 polyunsaturated fatty
acids and fish in human colon cells









Dissertation
for obtaining the degree of
doctor rerum naturalium (Dr. rer. nat.)

at the
Faculty of Biology and Pharmacy,
Friedrich-Schiller-University Jena

submitted by
Dipl. troph. Nina Habermann

stborn on 31 of August 1979
at Eisenach, Germany




















Reviewer:

st1 reviewer: PD Dr. Michael Glei, Jena
nd2 reviewer: Prof. Dr. Gerhard Jahreis, Jena
rd3 reviewer (external): Prof. Dr. Gerhard Eisenbrand, Kaiserslautern


date of the public disputation: 21.01.2010
Table of contents
Table of contents
Abbreviations ....................................................................................................... IV
List of Figures .... VII
List of Tables ....... IX
1. PREFACE ........................................................................................................ 1
1.1 Colorectal cancer ................... 1
1.1.1 Epidemiology and causes of colorectal cancer .......................... 1
1.1.2 Organisation of human colonic crypts ........................................ 3
1.1.3 Molecular changes during colon carcinogenesis ...................... 4
1.2 Dietary factors modulating colorectal cancer risk .......................... 8
1.2.1 General considerations and recommendations ......................... 8
1.2.1.1 Digestion and bioavailability of fat ...................................... 9
1.2.1.2 Nomenclature, and dietary sources of polyunsaturated
fatty acids ................................................................. 10
1.2.1.3 Metabolism of polyunsaturated fatty acids ....................... 11
1.2.1.4 Eicosanoid synthesis ............................................................. 13
1.3 Molecular mechanisms of colon cancer chemoprevention .......... 15
1.3.1 Modification of biotransformation enzymes and antioxidative
defence ......................................................................................................... 16
1.3.1.1 Modification of glutathione S-transferase T2 expression ..
.. 16
1.3.1.2 Modification of superoxide dismutase 2 expression ....... 17
1.3.1.3 Modification of cyclooxygenase-2 expression ................... 18
1.3.2 Induction of apoptosis ................................................................. 19
1.4 Use of faecal water as biomarkers for colorectal carcinogenesis 21
1.5 The FISHGASTRO human intervention study . 22
2. OBJECTIVES ................................................................................................ 24
3. PUBLICATIONS ........................... 26


I Table of contents
3.1 Publication I: N. Habermann, B. Christian, B. Luckas, B. L. Pool-Zobel,
E. K. Lund, M. Glei: „Effects of fatty acids on metabolism and cell growth
of human colon cell lines of different transformation state.” BioFactors
(2009) 35:460-467. ............................................................................................ 26
3.2 Publication II: N. Habermann, E.K. Lund, B. L. Pool-Zobel, M. Glei:
„Modulation of gene expression in eicosapentaenoic acid and
docosahexaenoic acid treated human colon adenoma cells.” Genes and
Nutrition (2009) 4:73–76. ................................................................................. 35
3.3 Publication III: N. Habermann, J. Helmbrecht, M. Glei: “Omega-3
polyunsaturated fatty acids alter SOD2, GSTT2 and COX2 in colorectal
cell lines.” Manuscript submitted to the British Journal of Nutrition. ........... 40
3.4 Publication IV: N. Habermann, A. Schön, E. K. Lund, M. Glei: „Fish
fatty acids alter markers of apoptosis in colorectal cell lines but fish
consumption has no impact on apoptosis-induction ex vivo.” accepted by
Apoptosis, DOI: 10.1007/s10495-010-0459-y. .................................................. 60
13.5 Publication V: G.K. Pot / N. Habermann , G. Majsak-Newman,
L. J. Harvey, A. Geelen, K. Przybylska-Philips, F. M. Nagengast, B. J. M.
Witteman, P. C. van de Meeberg, A. R. Hart, G. Schaafsma, G. Hooiveld, M.
Glei, E. K. Lund, B. L. Pool-Zobel, E. Kampman: “Increasing fish
consumption does not affect genotoxicity markers in the colon in an
intervention study.” accepted by Carcinogenesis, DOI:
10.1093/carcin/bgp255 ..................................................................................... 71
4. ADDITIONAL RESULTS ............. 91
4.1 Modulation of LT97 global gene expression by faecal water ....... 91
5. DISCUSSION ................................................................................................ 94
5.1 Chemopreventive mechanisms of n-3 PUFAs in vitro .................... 94
5.1.1 n-3 PUFA impair cell number by affecting cell growth and
apoptosis ...................................................................................................... 95
5.1.2 Gene expression alteration by n-3 PUFAs 98
5.1.3 Modulation of expression of antioxidative and inflammatory
enzymes by n-3 PUFAs ............................................................................. 100
5.2 Alteration of markers of chemoprevention after fish consumption
by faecal water ex vivo ................. 103
5.2.1 Ex vivo effects of faecal water on the modulation of DNA-
damaging effects, apoptosis-inducing potential, and global gene
expression .................................................................................................. 105
5.2.2 Evaluation of faecal water as a biomarker of colon cancer risk
within a fish-intervention trial ............................... 108
II Table of contents
6. SUMMARY AND FUTURE PERSPECTIVES ........................................... 113
7. ABSTRACT ................................................................. 116
8. ZUSAMMENFASSUNG ............................................. 118
9. APPENDIX .. 120
9.1 Affymetrix data on LT97 global gene expression modulation.... 120
9.2 Preliminary experiments on faecal water ...................................... 123
9.2.1 Modulation of LT97 cell growth ............... 123
9.2.2 Modulation of apoptosis in LT97 cells .................................... 124
9.2.3 Genotoxicity of faecal water (concentration series) ............. 125
9.3 Antigenotoxicity against hydrogen peroxide induced DNA damage
of faecal water from the FISHGASTRO study .......................................... 126
10. REFERENCES ......................................................................................... 127
ACKNOWLEDGEMENTS ...................... i
CURRICULUM VITAE .......................................................................................... ii
LIST OF POSTERS AND PUBLICATIONS ........................ iii
CERTIFICATION OF ORIGINALITY.................................................................. vii


III abbreviations
Abbreviations
AP-1 activator protein-1
ABC ATP binding cassette transporter
ACBP acyl-CoA binding protein
ADP adenosine diphosphate
AICR American Institute for Cancer Research
ALA α-linolenic acid
Apaf-1 apoptotic peptidase activating factor-1
APC Adenomatous Polyposis Coli
ARA arachidonic acid
ATP adenosine triphosphate
Bad Bcl-2-associated agonist of cell death
Bak Bcl-2-antagonist/killer
Bax Bcl-2-associated X protein
Bcl-2 B-cell chronic lymphocytic leukemia/lymphoma 2
BH Bcl-2 homology domain
Bid BH3 interacting domain death agonist
Bik Bcl-2-interacting killer
C carbon atom, refers to the carbon chain length of the fatty acid
CKI casein synthase kinase
COX cyclooxygenase
CpG cytosine-guanine dinucleoside
CYP cytochrome p450
d day
DAPI 4',6-Diamidino-2-phenylindole dihydrochloride
DCC Deleted in colorectal carcinoma
DGLA dihomo-γ-linoleic acid
DHA docosahexaenoic acid
DISC death-inducing signal complex
DR death receptor
DRI Dietary Reference Intake
DPA docosapentaenoic acid
EC Enzyme Commission number, a numerical classification scheme
for enzymes
EC half maximal effective concentration 50
EET epoxyeicosatetraenic acid
e.g. exempli gratia (for example)
EGFR epidermal growth factor receptor
EPA eicosapentaenoic acid
EpRE electrophilic responsive element
et al. et alii (and others)
etc. et cetera (and so forth)
FABS fatty acid binding proteins
FADD Fas-associated protein with death domain
FAP Familial Adenomatous Polyposis
Fas TNF