The potential of the human kidney cell line, Caki-1, as an in vitro screening system for drug interactions with organic cation transporters [Elektronische Ressource] / Natalie Glube
109 pages
English

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The potential of the human kidney cell line, Caki-1, as an in vitro screening system for drug interactions with organic cation transporters [Elektronische Ressource] / Natalie Glube

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The potential of the human kidney cell line, Caki-1, as an in vitro screening system for drug interactions with organic cation transporters Dissertation zur Erlangung des Grades „Doktor der Naturwissenschaften“ am Fachbereich Chemie, Pharmazie und Geowissenschaften der Johannes Gutenberg-Universität Mainz Natalie Glube, BSc. geb. in Halifax, Canada Mainz, 2007 Tag der mündlichen Prüfung: September 14, 2007 “research is discovering God’s secrets” 7Table of Contents Abbreviations....................................................................................................................11 1. Introduction...................................................................................................................15 1.1 The pharmacological role of the kidney .....................................................................15 1.1.1 General structural and functional organization of the kidney ...............................15 1.1.2 General functions of the kidney ...........................................................................16 1.1.3 Renal drug-handling processes (renal clearance) ...............................................16 1.1.4 Glomerular filtration (GF).....................................................................................17 1.1.5 Tubular secretion.................................................................................................17 1.1.6 Tubular reabsorption................

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Publié par
Publié le 01 janvier 2007
Nombre de lectures 9
Langue English
Poids de l'ouvrage 3 Mo

Extrait

The potential of the human kidney cell line, Caki-1, as an in vitro screening
system for drug interactions with organic cation transporters

Dissertation
zur Erlangung des Grades
„Doktor der Naturwissenschaften“

am Fachbereich Chemie, Pharmazie und Geowissenschaften
der Johannes Gutenberg-Universität Mainz

Natalie Glube, BSc.

geb. in Halifax, Canada

Mainz, 2007
Tag der mündlichen Prüfung: September 14, 2007
“research is discovering God’s secrets”
7
Table of Contents

Abbreviations....................................................................................................................11
1. Introduction...................................................................................................................15
1.1 The pharmacological role of the kidney .....................................................................15
1.1.1 General structural and functional organization of the kidney ...............................15
1.1.2 General functions of the kidney ...........................................................................16
1.1.3 Renal drug-handling processes (renal clearance) ...............................................16
1.1.4 Glomerular filtration (GF).....................................................................................17
1.1.5 Tubular secretion.................................................................................................17
1.1.6 Tubular reabsorption............................................................................................17
1.2 Proximal tubule (PT) epithelium.................................................................................17
1.2.1 Morphological, biochemical and electrophysiological characteristics of the PT
epithelium .....................................................................................................................17
1.2.2 Carrier-mediated drug transport in the PT epithelium..........................................19
1.2.3 PT Drug Metabolism............................................................................................20
1.3 Drug Transporters......................................................................................................20
1.3.1 General characteristics of drug transporters........................................................20
1.3.2 Transporter expression in the PT.........................................................................21
1.3.3 ABC transporters .................................................................................................22
1.3.4 SLC and SLCO transporters................................................................................22
1.3.5 Organic Cation Transporters (OCTs): structure, function, physiological roles and
biopharmaceutical implications.....................................................................................22
1.3.5.1 Cloning of the polyspecific organic cation transporters: OCTs, OCTNs and
MATEs.......................................................................................................................25
1.3.5.2 MATE transporters.........................................................................................26
1.3.5.2 Tissue distribution and membrane localization (see Figure 1.5 for an
overview) ...................................................................................................................26
1.3.5.3 Functional properties and substrate specificities ...........................................28
1.3.5.4 Substrate and inhibitor specificities of the individual OCTs ...........................28
1.3.5.5 Function and substrate specificities of OCTN1 and OCTN2..........................28
1.3.5.6 Function and specificity of MATE transporters...............................................29
1.3.5.7 Function of polyspecific OCTs in the kidney ..................................................29
1.3.5.8 Biomedical implications of polyspecific OCTs in the kidney...........................30
1.4 Drug-drug interactions (DDIs) in the PT via transport proteins ..................................30
1.4.1 Interactions involving OCTs.................................................................................30
1.5 In vitro model systems for studying the PT epithelium and more specifically drug
transport in the PT ...........................................................................................................31
1.5.1 Experimental considerations................................................................................32
1.5.2 Higher-order experimental systems.....................................................................32
1.5.3 Cell culture models ..............................................................................................33
1.5.3.1 Primary PT cell cultures.................................................................................34
1.5.3.2 PT cell lines ...................................................................................................34
1.5.3.3 Membrane vesicles........................................................................................34
1.5.3.4 In vitro systems for OC transport ...................................................................35 8
2. Aims of the thesis........................................................................................................ 37
3. Caki-1 cells represent an in vitro model system for studying the human proximal
tubule epithelium ............................................................................................................. 39
3.1 Abstract..................................................................................................................... 40
3.2 Introduction ............................................................................................................... 40
3.3 Methods .................................................................................................................... 41
3.4 Results...................................................................................................................... 44
3.5 Discussion ................................................................................................................ 48
3.6 Acknowledgements................................................................................................... 51

4. mRNA expression profiles of ATP-binding Cassette, Solute Carrier and Organic
Anion Transporting Polypeptide transporters and Cytochrome P450 metabolizing
enzymes in Caki-1 and primary human proximal tubule cells ..................................... 53
4.1 Abstract..................................................................................................................... 54
4.2 Introduction ............................................................................................................... 54
4.3 Materials and Methods.............................................................................................. 56
4.4 Results...................................................................................................................... 58
4.5 Discussion ................................................................................................................ 61

5. OCTN2 mediated carnitine uptake in a newly discovered human proximal tubule
cell line (Caki-1) ............................................................................................................... 65
5.1 Abstract..................................................................................................................... 66
5.2 Figures and Tables from Mol Pharm. 2007 Jan-Feb;4(1):160-8 ............................... 66
5.3 Correlation of data between Caki-1 and human primary proximal tubule cells (HPT)71
5.3.1 OCTN2 protein expression in HPT cells ............................................................. 72
5.3.2 Functional activity of OCTN2 in HPT cells and comparison to Caki-1 cells ...... 72
5.3.3 Conclusions in respect to the correlation of data between HPT and Caki-1 cells 73

6. Caki-1 cells as a model system for the interaction of renally secreted drugs with
OCT3 ................................................................................................................................. 75
6.1 Abstract..................................................................................................................... 76
6.2 Introduction ............................................................................................................... 76
6.3 Materials and Methods.............................................................................................. 78
6.4 Results...................................................................................................................... 80
6.5 Discussion ................................................................................................................ 84
6.6 Acknowledgements................................................................................................... 88

Summary .......................................................................................................................... 89
Zusammenfassung ...............................................................................................

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