JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 13, 2006; DOI: 10.1124/jpet.105.094193

This Article
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
jpet.105.094193v1
317/1/378    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Author home page(s):
Christina Ziemann
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ziemann, C.
Right arrow Articles by Hirsch-Ernst, K. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ziemann, C.
Right arrow Articles by Hirsch-Ernst, K. I.


Received for publication August 12, 2005.
Revised January 12, 2006.
Accepted for publication January 12, 2006.

The Role of Prostaglandin E-Receptor-Dependent Signaling via cAMP in Mdr1b Gene Activation in Primary Rat Hepatocyte Cultures

Christina Ziemann 1*, Armin Riecke 2, Gudrun Rudell 2, Elke Oetjen 3, Hans J. Steinfelder 3, Christian Lass 2, Georg F. Kahl 2, Karen I. Hirsch-Ernst 2

1 Fraunhofer ITEM and Toxicology, University of Gottingen 2 Toxicology, University of Gottingen 3 Molecular Pharmacology, University of Gottingen

* Address correspondence to: E-mail: ziemann{at}item.fraunhofer.de

Abstract

Multidrug resistance (mdr) proteins of the mdr1-type function as multi-specific xenobiotic transporters in hepatocytes. In the liver, mdr1 overexpression occurs during regeneration, cirrhosis, and hepatocarcinogenesis and may contribute to primary chemotherapy resistance. Cultured rat hepatocytes exhibit time-dependent "intrinsic" increase in functional mdr1b expression, which depends on cyclooxygenase-catalyzed prostaglandin E2 release. In the present study, the prostaglandin E (EP)-receptor agonist misoprostol (1-10 µg/ml) further enhanced intrinsic mdr1b mRNA expression in primary rat hepatocytes. On the other hand, AH23848B (30 µmol/L), an antagonist of the cAMP-coupled EP4-receptor, and the protein kinase A (PKA) inhibitor H89 (10nmol/L) repressed intrinsic mdr1b mRNA up-regulation, whereas the stable cAMP analogue 8 bromo-cAMP (10 µmol/L) and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 µmol/L) further enhanced intrinsic mdr1b expression. Primary rat hepatocytes, transiently transfected with reporter gene constructs, controlled by mdr1b 5'-gene-flanking regions (1074 to +154 bp or -250 to +154 bp), demonstrated pronounced mdr1b promoter activity, already without addition of exogenous modulators. Nevertheless, activity was further stimulated by misoprostol, 8 bromo-cAMP or IBMX. Co-transfection with expression vectors for PKI, an inhibitor protein of cAMP-dependent PKA, or KCREB, a dominant-negative mutant of the cAMP-responsive element-binding protein (CREB), decreased high intrinsic mdr1b promoter activity. KCREB also counteracted misoprostol-induced mdr1b promoter activation. In conclusion, these data provide evidence for a pivotal role of EP-receptor-stimulated, cAMP-dependent activation of PKA and CREB, or CREB-related proteins, in mdr1b gene activation in primary rat hepatocytes. Thus, these data might offer potential new target structures for the reversal of primary drug resistance of e.g. liver tumors.


Key words: CREB, P-glycoprotein, mdr1b promoter, multidrug resistance, prostaglandin E2, rat hepatocyte cultures


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
C. Chen, X. Cheng, M. Z. Dieter, Y. Tanaka, and C. D. Klaassen
Activation of cAMP-Dependent Signaling Pathway Induces Mouse Organic Anion Transporting Polypeptide 2 Expression
Mol. Pharmacol., April 1, 2007; 71(4): 1159 - 1164.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.