Induction of ABCC3 (MRP3) by pregnane X receptor activators.

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Teng S, Jekerle V, Piquette-Miller M

Induction of ABCC3 (MRP3) by pregnane X receptor activators.

Drug Metab Dispos. 2003 Nov;31(11):1296-9.

PubMed ID

14570758 [ View in PubMed

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Abstract

The pregnane X receptor (PXR) mediates the induction of various genes by xenobiotics, including several ATP-binding cassette transporters. PXR is also activated by bile acids likely to prevent their accumulation to toxic levels; however, the role of PXR in the regulation of MRP3, an important bile acid efflux transporter, has not been elucidated. The impact of PXR activators on the hepatic expression of MRP3 was examined in vivo and in vitro. The human hepatoma cell lines HuH7 and HepG2 were treated with PXR activators including clotrimazole, rifampicin, 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl]estra-4,9-dien-3-one (RU486), metyrapone, nifedipine, lithocholic acid, and 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (PCN). Levels of MRP3 mRNA, as determined by reverse transcription-polymerase chain reaction, were induced 1.6- to 8-fold in a dose-dependent manner (p < 0.05). Corresponding decreases in the multidrug resistance-associated protein-dependent cellular retention of 5-carboxyfluorescein were also seen in the treated HuH7 cells. In vivo studies demonstrated increased PXR mRNA and induction of MRP3 mRNA in the livers of wild-type mice treated with the PXR activator RU486. On the other hand, MRP3 induction was not seen in the RU486-treated PXR-null mice. These results suggest that PXR activation may play a role in the regulation of MRP3 expression.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Metyrapone	Canalicular multispecific organic anion transporter 2	Protein	Humans	Unknown	Inducer	Details
Nifedipine	Canalicular multispecific organic anion transporter 2	Protein	Humans	Unknown	Inducer	Details
Rifampicin	Canalicular multispecific organic anion transporter 2	Protein	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Metyrapone	Approved Investigational	ABCC3	8714	upregulated	[Metyrapone results in increased activity of NR1I2 protein] which results in increased expression of ABCC3 mRNA	17q21.33
Metyrapone	Approved Investigational	ABCC3	8714	upregulated	Metyrapone results in increased expression of ABCC3 mRNA	17q21.33
Mifepristone	Approved Investigational	ABCC3	8714	upregulated	[Mifepristone results in increased activity of NR1I2 protein] which results in increased expression of ABCC3 mRNA	17q21.33
Mifepristone	Approved Investigational	ABCC3	8714	upregulated	Mifepristone results in increased expression of ABCC3 mRNA	17q21.33
Nifedipine	Approved	ABCC3	8714	upregulated	[Nifedipine results in increased activity of NR1I2 protein] which results in increased expression of ABCC3 mRNA	17q21.33
Nifedipine	Approved	ABCC3	8714	upregulated	Nifedipine results in increased expression of ABCC3 mRNA	17q21.33
Rifampicin	Approved	ABCC3	8714	upregulated	[Rifampin results in increased activity of NR1I2 protein] which results in increased expression of ABCC3 mRNA	17q21.33
Rifampicin	Approved	ABCC3	8714	upregulated	Rifampin results in increased expression of ABCC3 mRNA	17q21.33