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Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84)
I S Haslam1, K Jones, T Coleman
1Epithelial Research Group, Institute for Cell and Molecular Biosciences, University of Newcastle Upon Tyne, Medical School, Newcastle Upon Tyne NE24HH, UK.
Biochemical Pharmacology
|August 16, 2008
Summary
Certain drugs can induce P-glycoprotein (Pgp) in the intestine, affecting oral drug availability and interactions. This study investigated Pgp induction by various compounds in intestinal cells, revealing complex regulatory mechanisms.
Area of Science:
- Pharmacology
- Molecular Biology
- Cell Biology
Background:
- Intestinal P-glycoprotein (Pgp; MDR1) induction impacts oral drug bioavailability and can cause drug-drug interactions.
- Understanding Pgp regulation is crucial for predicting drug efficacy and safety.
- Previous studies highlight Pgp's role in drug transport and metabolism.
Purpose of the Study:
- To investigate the induction of P-glycoprotein (Pgp) activity in a human intestinal cell line (T84) after pre-exposure to various drug compounds.
- To assess Pgp substrate interactions and inhibition using MDR1-transfected MDCKII cells.
- To examine changes in gene expression, including MDR1, MRP2, PXR, and CAR.
Main Methods:
- Utilized human MDR1-transfected MDCKII epithelial monolayers to evaluate Pgp substrate interactions and digoxin secretion inhibition.
- Employed the T84 cell line to assess Pgp-mediated digoxin secretion induction following pre-exposure to drug compounds.
- Quantified changes in MDR1, MRP2, PXR, and CAR gene expression using quantitative RT-PCR.
Main Results:
- Pre-exposure to the PXR activator hyperforin increased net transepithelial digoxin secretion and MDR1 mRNA expression.
- Several Pgp substrates, including quinidine and atorvastatin, induced digoxin secretion, with some also elevating MDR1 mRNA levels.
- A strong correlation was observed between drug modulation of MRP2 and PXR mRNA expression.
Conclusions:
- Drug-induced Pgp activity in intestinal cells can be modulated by various compounds, affecting drug transport.
- Observed induction of digoxin secretion by certain Pgp substrates suggests potential post-translational regulation mechanisms.
- The correlation between MRP2 and PXR mRNA modulation indicates complex regulatory networks involved in drug response.
