Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (57)
Right arrowRequest Permissions
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.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Carcinogenesis, Vol. 20, No. 3, 407-414, March 1999
© 1999 Oxford University Press

Reactive oxygen species participate in mdr1b mRNA and P-glycoprotein overexpression in primary rat hepatocyte cultures

Christina Ziemann, Alexander Bürkle1, Georg F. Kahl and Karen I. Hirsch-Ernst2

Department of Toxicology, Institute of Pharmacology and Toxicology, University of Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany and
1 Division F0100, German Cancer Research Centre, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany

P-glycoproteins encoded by multidrug resistance type 1 (mdr1) genes mediate ATP-dependent efflux of numerous lipophilic xenobiotics, including several anticancer drugs, from cells. Overexpression of mdr1-type transporters in tumour cells contributes to a multidrug resistance phenotype. Several factors shown to induce mdr1 overexpression (UV irradiation, epidermal growth factor, tumour necrosis factor {alpha}, doxorubicin) have been associated with the generation of reactive oxygen species (ROS). In the present study, primary rat hepatocyte cultures that exhibit time-dependent overexpression of the mdr1b gene were used as a model system to investigate whether ROS might participate in the regulation of intrinsic mdr1b overexpression. Addition of H2O2 to the culture medium resulted in a significant increase in mdr1b mRNA and P-glycoprotein after 3 days of culture, with maximal (~2-fold) induction being observed with 0.5–1 mM H2O2. Furthermore, H2O2 led to activation of poly(ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, indicating that ROS reached the nuclear compartment. Thus, extracellularly applied H2O2 elicited intracellular effects. Treatment of rat hepatocytes with the catalase inhibitor 3-amino-1,2,4-triazole (2–4 mM for 72 h or 10 mM for 1 h following the hepatocyte attachment period) also led to an up-regulation of mdr1b mRNA and P-glycoprotein expression. Conversely, antioxidants (1 mM ascorbate, 10 mM mannitol, 2% dimethyl sulphoxide, 10 mM N-acetylcysteine) markedly suppressed intrinsic mdr1b mRNA and P-glycoprotein overexpression. Intracellular steady-state levels of the mdr1 substrate rhodamine 123, determined as parameter of mdr1-type transport activity, indicated that mdr1-dependent efflux was increased in hepatocytes pretreated with H2O2 or aminotriazole and decreased in antioxidant-treated cells. The induction of mdr1b mRNA and of functionally active mdr1-type P-glycoproteins by elevation in intracellular ROS levels and the repression of intrinsic mdr1b mRNA and P-glycoprotein overexpression by antioxidant compounds support the conclusion that the expression of the mdr1b P-glycoprotein is regulated in a redox-sensitive manner.

Abbreviations: 3-AB, 3-aminobenzamide; AP-1, activator protein-1; AT, 3-amino-1,2,4-triazole; DMSO, dimethyl sulphoxide; EGF, epidermal growth factor; mdr, multidrug resistance; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NF-{kappa}B, nuclear factor {kappa}B; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; P-gp, P-glycoprotein; ROS, reactive oxygen species; SDS, sodium dodecyl sulphate; SSC, standard saline citrate; TNF-{alpha}, tumour necrosis factor alpha.

2 To whom correspondence should be addressed Email: khirsche{at}med.uni-goettingen.de


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Antimicrob ChemotherHome page
E. Papp, I. Gadawski, and H. C. F. Cote
Longitudinal effects of thymidine analogues on mtDNA, mtRNA and multidrug resistance (MDR-1) induction in cultured cells
J. Antimicrob. Chemother., May 1, 2008; 61(5): 1048 - 1052.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
R. Callaghan, E. Crowley, S. Potter, and I. D. Kerr
P-glycoprotein: So Many Ways to Turn It On
J. Clin. Pharmacol., March 1, 2008; 48(3): 365 - 378.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
Y. Abdul Jalil, V. Ritz, A. Jakimenko, C. Schmitz-Salue, H. Siebert, D. Awuah, A. Kotthaus, T. Kietzmann, C. Ziemann, and K. I. Hirsch-Ernst
Vesicular localization of the rat ATP-binding cassette half-transporter rAbcb6
Am J Physiol Cell Physiol, February 1, 2008; 294(2): C579 - C590.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
A. Gomez-Martinez, P. Garcia-Morales, A. Carrato, M. D. Castro-Galache, J. L. Soto, E. Carrasco-Garcia, M. Garcia-Bautista, P. Guaraz, J. A. Ferragut, and M. Saceda
Post-transcriptional Regulation of P-Glycoprotein Expression in Cancer Cell Lines
Mol. Cancer Res., June 1, 2007; 5(6): 641 - 653.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. Ziemann, A. Riecke, G. Rudell, E. Oetjen, H. J. Steinfelder, C. Lass, G. F. Kahl, and K. I. Hirsch-Ernst
The Role of Prostaglandin E Receptor-Dependent Signaling via cAMP in Mdr1b Gene Activation in Primary Rat Hepatocyte Cultures
J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 378 - 386.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
U. Puhlmann, C. Ziemann, G. Ruedell, H. Vorwerk, D. Schaefer, C. Langebrake, P. Schuermann, U. Creutzig, and D. Reinhardt
Impact of the Cyclooxygenase System on Doxorubicin-Induced Functional Multidrug Resistance 1 Overexpression and Doxorubicin Sensitivity in Acute Myeloid Leukemic HL-60 Cells
J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 346 - 354.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Ledoux, R. Yang, G. Friedlander, and D. Laouari
Glucose Depletion Enhances P-Glycoprotein Expression in Hepatoma Cells: Role of Endoplasmic Reticulum Stress Response
Cancer Res., November 1, 2003; 63(21): 7284 - 7290.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H.-J. Cho, H. G. Jeong, J.-S. Lee, E.-R. Woo, J.-W. Hyun, M.-H. Chung, and H. J. You
Oncogenic H-Ras Enhances DNA Repair through the Ras/Phosphatidylinositol 3-Kinase/Rac1 Pathway in NIH3T3 Cells. EVIDENCE FOR ASSOCIATION WITH REACTIVE OXYGEN SPECIES
J. Biol. Chem., May 24, 2002; 277(22): 19358 - 19366.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
S. De Flora, A. Izzotti, F. D'Agostini, and R. M. Balansky
Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points
Carcinogenesis, July 1, 2001; 22(7): 999 - 1013.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
K. I. Hirsch-Ernst, K. Schlaefer, D. Bauer, A. F. Heder, and G. F. Kahl
Repression of Phenobarbital-Dependent CYP2B1 mRNA Induction by Reactive Oxygen Species in Primary Rat Hepatocyte Cultures
Mol. Pharmacol., June 1, 2001; 59(6): 1402 - 1409.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
M. Wartenberg, F. C. Ling, M. Schallenberg, A. T. Baumer, K. Petrat, J. Hescheler, and H. Sauer
Down-regulation of Intrinsic P-glycoprotein Expression in Multicellular Prostate Tumor Spheroids by Reactive Oxygen Species
J. Biol. Chem., May 11, 2001; 276(20): 17420 - 17428.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.