Hagenbuch
Fakultäten » Medizinische Fakultät » Klinische Pharmakologie und Toxikologie, Klinik für » Prof. Dr. Gerd Kullak-Ublick » Hagenbuch
Completed research project
| Title / Titel | Molecular physiology of bile acid, organic anion and drug transport within the enterohepatic circulation | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Original title / Originaltitel | Molecular physiology of bile acid, organic anion and drug transport within the enterohepatic circulation | ||||||
| Summary / Zusammenfassung | The enterohepatic circulation of bile acids is maintained by several specific transport systems located in the apical and basolateral membranes of hepatocytes.In rodent (mouse, rat) liver, Na+-dependent (Ntcp) as well as Na+-independent (Oatp1/Oatp2/Oatp4) transport systems are involved in uptake of bile acids across the basolateral membrane, while the exit step across the canalicular membrane is mediated by the ATP-dependent bile salt export pump (Bsep). In addition to bile acids, Oatps are also involved in the uptake of numerous amphipathic drugs into liver cells. To understand the physiology and pathophysiology of enterohepatic circulation of bile acids and drugs, the involved transport systems have to be identified and characterized at the molecular level. The specific aims of the project are the following: 1) We will study the physiologic relevance of mouse Ntcp by disruption of its gene (generation of Ntcp knock-out mouse).This will also allow to determine whether the liver has additional sodium-dependent transport systems for bile salts and whether the absence of Ntcp results in pathological conditions such as cholestasis. 2) We will investigate the molecular mechanisms and physiologic significance of Oatp1-, Oatp2- and Oatp4--mediated transport in the liver. Especially, the regulation of Oatp expression will be studied in several animal models. On the genomic level, identification of important transcription factors should allow us to learn more about expression of the Oatp genes in various physiological and pathophysiological conditions. And 3) We will search for new Oatps with special emphasis on the identification of human orthologues in rat and mouse and compare their regulation of expression with man. The proposed research has significance for better understanding of the physiology and pathophysiology of the enterohepatic circulation, and the molecular mechanisms involved in the hepatic clearance of drugs and numerous toxins. Weitere Informationen |
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| Publications / Publikationen | Hagenbuch, B., I.D. Adler and T.E. Schmid: Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X, Biochem. J. 345:115-120, 2000Cattori V, Eckhardt U, Hagenbuch B: Molecular cloning and functional characterization of two alternatively spliced Ntcp isoforms from mouse liver, Biochim. Biophys. Acta, 1445:154-159, 1999Eckhardt U, Schroeder A, Stieger B, Höchli M, Landmann L, Tynes R, Meier PJ, Hagenbuch B.: Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells, Am. J. Physiol., 276:G1037-G1042, 1999Weitere Informationen | ||||||
| Keywords / Suchbegriffe | Molecular Medicine, Liver Transport Physiology, Bile Acid Transport, Hepatic Drug Clearance, | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.pharmakologie.usz.ch/LehreUndForschung/Forschung/Seiten/default.aspx | ||||||
| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Apr 2000 to Jun 2003 |