Haslam, Iain S., Jones, K., Coleman, T. and Simmons, N.L. (2008) Rifampin and digoxin induction of MDR1 expression and function in human intestinal (T84) epithelial cells. British Journal of Pharmacology, 154 (1). pp. 246-255. ISSN 0007-1188
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BACKGROUND AND PURPOSE
Oral drug bioavailability is limited by intestinal expression of P-glycoprotein (MDR1, Pgp, ABCB1) whose capacity is regulated via nuclear receptors e.g. the pregnane X receptor (PXR, SXR, NR1I2). In order to study dynamic regulation of MDR1 transport capacity we have identified the T84 epithelial cell-line as a model for human intestine co-expressing MDR1 with PXR. The ability of rifampin, a known PXR agonist and digoxin, a model MDR1 substrate, to regulate MDR1 expression and transport activity has been tested, in these T84 cells.
Transport was assayed by bi-directional [(3)H]-digoxin transepithelial fluxes across epithelial layers of T84 cells seeded onto permeable filter supports following pre-exposure to rifampin and digoxin. Quantitative real-time PCR, Western blotting and immunocytochemistry were used to correlate induction of MDR1 transcript and protein levels with transport activity.
Rifampin exposure (10 microM, 72 hours) increased MDR1 transcript levels (3.4 fold), MDR1 total protein levels (4.4 fold), apical MDR1 protein (2.7 fold) and functional activity of MDR1 (1.2 fold). Pre-incubation with digoxin (1 microM, 72 hours) potently induced MDR1 transcript levels (92 fold), total protein (7 fold), apical MDR1 protein (4.7 fold) and functional activity (1.75 fold). Whereas PXR expression was increased by rifampin incubation (2 fold), digoxin reduced PXR expression (0.3 fold).
CONCLUSIONS AND IMPLICATIONS
Chronic digoxin pre-treatment markedly upregulates MDR1 expression and secretory capacity of T84 epithelia. Digoxin-induced changes in MDR1 levels are distinct from PXR-mediated changes resulting from rifampin exposure.
|Subjects:||Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
|Schools:||School of Applied Sciences
School of Applied Sciences > Biomolecular Sciences Research Centre
|Depositing User:||Iain Haslam|
|Date Deposited:||11 Nov 2015 10:09|
|Last Modified:||06 Dec 2015 19:52|
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