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

• Published in: Toxicology (Amsterdam) Vol. 171; no. 2; pp. 137 - 146
• Main Authors: Kauffmann, Hans-Martin, Pfannschmidt, Sylvia, Zöller, Heike, Benz, Anke, Vorderstemann, Birgit, Webster, Jeanette I, Schrenk, Dieter
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 28.02.2002; Amsterdam Elsevier Science
• Subjects: Arsenites - pharmacology; Biological and medical sciences; Cell Line; Clotrimazole - pharmacology; DNA-Binding Proteins - analysis; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Gene expression; Gene Expression Regulation - drug effects; General aspects. Methods; Genes, Reporter; Humans; Hydroquinones - pharmacology; Induction; Medical sciences; Medicin och hälsovetenskap; Mitochondrial Proteins; Multidrug resistance protein 1 (MRP1); Multidrug resistance protein 2 (MRP2); Multidrug Resistance-Associated Proteins; MutS Homolog 3 Protein; Oxidation-Reduction; Pregnane X Receptor; Quercetin - pharmacology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Steroid - agonists; Ribosomal Proteins - analysis; Ribosomal Proteins - biosynthesis; Ribosomal Proteins - genetics; Rifampin - pharmacology; RNA, Messenger - analysis; Saccharomyces cerevisiae Proteins; Toxicology; Multidrug resistance protein 2 (MRP2); Multidrug resistance protein 1 (MRP1); ARE, antioxidative response element; Induction; PXR, pregnane X receptor; tBHQ, tert-butylated hydroquinone; MRP, multidrug resistance protein; Gene expression; Pregnane; Gene; Activator; Chemical compound; Multiple resistance; In vitro; ABC transporter; Protein; Hormonal receptor
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(01)00570-4

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.