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Phenobarbital alters hepatic Mrp2 function by direct and indirect interactions.
Nita J Patel1, Maciej J Zamek-Gliszczynski, Peijin Zhang
1Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Molecular Pharmacology
|June 20, 2003
Summary
Phenobarbital (PB) impairs organic anion excretion by competing for biliary transport and reducing Mrp2 protein levels. This study investigated PB
Area of Science:
- Hepatology and Drug Metabolism
- Molecular Toxicology
- Pharmacokinetics
Background:
- Phenobarbital (PB) treatment is known to affect the biliary excretion of organic anions.
- Potential mechanisms include direct competition for excretion or alterations in hepatic transport proteins.
- The role of multidrug resistance-associated protein 2 (Mrp2) in PB's effects requires further elucidation.
Purpose of the Study:
- To investigate the role of Mrp2 in the biliary excretion of phenobarbital and its metabolites.
- To determine how PB treatment influences Mrp2 expression and function.
- To elucidate the mechanisms by which PB impairs organic anion biliary excretion.
Main Methods:
- Utilized isolated perfused livers (IPLs) from Wistar and Mrp2-deficient TR- rats.
- Quantified biliary excretion of PB metabolites (PBOH-glucuronide, PBOH-sulfate).
- Assessed Mrp2 mRNA and protein expression following PB treatment and washout periods.
- Measured the biliary excretion of a known Mrp2 substrate, 5-(and-6)-carboxy-2',7'-dichlorofluorescein (CDCF).
Main Results:
- In normal livers, PB metabolites PBOH-glucuronide and PBOH-sulfate were excreted in bile; only PBOH-sulfate was found in TR- rat bile.
- PB pretreatment increased Mrp2 mRNA, but protein levels showed complex changes with a significant decrease after 48-h washout.
- Biliary excretion of the Mrp2 substrate CDCF was significantly reduced in livers from PB-treated rats after a 48-h washout.
Conclusions:
- Phenobarbital's metabolite PBOH-glucuronide is a substrate for Mrp2, potentially competing with other organic anions.
- PB treatment leads to decreased Mrp2 protein expression and functional capacity 48 hours post-treatment.
- These findings support dual mechanisms for PB-induced impairment of organic anion biliary excretion: competitive inhibition and reduced transporter expression.