Endocrinology, Vol 133, 521-528, Copyright © 1993 by Endocrine Society

ARTICLES

Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells

JY Zhao, M Ikeguchi, T Eckersberg and MT Kuo
Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030.

Considerable evidence has accumulated indicating that overexpression of P-glycoproteins encoded by the multidrug-resistance (mdr) genes is responsible for the development of collateral resistance to a number of structurally and functionally dissimilar cytotoxic compounds in animal cells. There are three mdr genes (mdr1, mdr2, and mdr3) in the mouse genome and two (MDR1 and MDR2) in the human genome; however, only two mouse genes (mdr1 and mdr3) and one human gene (MDR1) can confer multidrug resistance upon transfection into otherwise drug-sensitive cells. Using RNase protection assay we report here that the steady- state levels of mdr1 and mdr3 messenger RNA were elevated in mouse hepatoma cells treated with dexamethasone (Dex); whereas no induction of mdr2 gene was found. Western blot analyses using anti-mdr1 and anti- mdr3 antibodies revealed that the encoded proteins appeared to be increased, but at much reduced levels. The induction was time and Dex concentration dependent. Nuclear run-on experiments demonstrated that the induction was at least in part by transcriptional control. The induction apparently required new protein synthesis since no increases in mdr1 and mdr3 transcripts was found when cultured cells were simultaneously treated with Dex and cycloheximide. Neither mdr1 nor mdr3 gene was induced in the Dex-treated nonhepatoma cell lines, LMtk- and NIH3T3. Similarly, MDR1 messenger RNA levels were elevated in the Dex-treated human hepatoma line, HepG2, but not in the nonhepatoma, HeLa. This study demonstrated that the hormonal regulation of mdr gene expression is gene and cell type specific.

This article has been cited by other articles:

				P. J. Mark, S. Augustus, J. L. Lewis, D. P. Hewitt, and B. J. Waddell Changes in the Placental Glucocorticoid Barrier During Rat Pregnancy: Impact on Placental Corticosterone Levels and Regulation by Progesterone Biol Reprod, June 1, 2009; 80(6): 1209 - 1215. [Abstract] [Full Text] [PDF]

				S. Lam, N. Partovi, L. S. Ting, and M. H. Ensom Corticosteroid Interactions with Cyclosporine, Tacrolimus, Mycophenolate, and Sirolimus: Fact or Fiction? Ann. Pharmacother., July 1, 2008; 42(7): 1037 - 1047. [Abstract] [Full Text] [PDF]

				B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]

				N. Nishio, T. Katsura, K. Ashida, M. Okuda, and K.-i. Inui MODULATION OF P-GLYCOPROTEIN EXPRESSION IN HYPERTHYROID RAT TISSUES Drug Metab. Dispos., November 1, 2005; 33(11): 1584 - 1587. [Abstract] [Full Text] [PDF]

				D. Anglicheau, M. Flamant, M. H. Schlageter, F. Martinez, B. Cassinat, P. Beaune, C. Legendre, and E. Thervet Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2409 - 2414. [Abstract] [Full Text] [PDF]

				G-T Ho, F M Moodie, and J Satsangi Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut, May 1, 2003; 52(5): 759 - 766. [Abstract] [Full Text]

				J. M. Brady, N. J. Cherrington, D. P. Hartley, S. C. Buist, N. Li, and C. D. Klaassen Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats Drug Metab. Dispos., July 1, 2002; 30(7): 838 - 844. [Abstract] [Full Text] [PDF]

				R. Yumoto, T. Murakami, M. Sanemasa, R. Nasu, J. Nagai, and M. Takano Pharmacokinetic Interaction of Cytochrome P450 3A-Related Compounds with Rhodamine 123, a P-Glycoprotein Substrate, in Rats Pretreated with Dexamethasone Drug Metab. Dispos., February 1, 2001; 29(2): 145 - 151. [Abstract] [Full Text]

				J.-M. Pascussi, L. Drocourt, J.-M. Fabre, P. Maurel, and M.-J. Vilarem Dexamethasone Induces Pregnane X Receptor and Retinoid X Receptor-alpha Expression in Human Hepatocytes: Synergistic Increase of CYP3A4 Induction by Pregnane X Receptor Activators Mol. Pharmacol., August 1, 2000; 58(2): 361 - 372. [Abstract] [Full Text]

				J. H. Lin, M. Chiba, and T. A. Baillie Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized? Pharmacol. Rev., June 1, 1999; 51(2): 135 - 158. [Abstract] [Full Text] [PDF]

				A. Geick, M. Eichelbaum, and O. Burk Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin J. Biol. Chem., April 27, 2001; 276(18): 14581 - 14587. [Abstract] [Full Text] [PDF]