Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression.

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Kauffmann HM, Pfannschmidt S, Zoller H, Benz A, Vorderstemann B, Webster JI, Schrenk D

Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression.

Toxicology. 2002 Feb 28;171(2-3):137-46.

PubMed ID

11836020 [ View in PubMed

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Abstract

In the present study, we investigated the inducibility of the drug conjugate transporter genes MRP1 and MRP2 by redox-active compounds such as tertiary butylated hydroquinone (tBHQ) and quercetin and by chemicals known to activate the pregnane X receptor (PXR) such as rifampicin and clotrimazol and by the metalloid compound arsenite. The human MRP2 gene was found to be inducible in HepG2 cells by rifampicin, clotrimazol, arsenite and tBHQ. As MRP1 expression is extremely low in HepG2 cells, its inducibility was studied in MCF-7 cells. However, only tBHQ and quercetin acted as inducers, but not the other compounds investigated. Reporter gene assays demonstrated that proximal promoter regions of the genes contribute to the induction by tBHQ, quercetin (MRP1) and clotrimazol (MRP2). However, the deletion of binding sites supposed to mediate the induction process (a PXR-binding element-like sequence for the clotrimazol effect and an ARE (antioxidative response element) for the tBHQ/quercetin effect) did not result in a significant decrease in the induction factor indicating that other parts of the promoter are probably involved in the induction process. In summary, expression of both genes can be up-regulated by redox-active compounds, while the other compounds tested induced only MRP2 but not MRP1 expression.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Arsenic trioxide	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Inducer	Details
Quercetin	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Inhibitor Inducer	Details
Rifampicin	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Clotrimazole	Approved Vet Approved	ABCC2	1244	upregulated	Clotrimazole results in increased expression of ABCC2 mRNA	10q24.2
Quercetin	Experimental Investigational	ABCC1	4363	upregulated	Quercetin results in increased expression of ABCC1 mRNA	16p13.11
Rifampicin	Approved	ABCC2	1244	upregulated	Rifampin results in increased expression of ABCC2 mRNA	10q24.2