Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor*

By H. R. Kast, B. Goodwin, Paul T. Tarr, Stacey A. Jones, A. Anisfeld, C. Stoltz, P. Tontonoz, S. Kliewer, T. Willson, P. Edwards. Journal of Biological Chemistry, 2002

961 citations recorded by the source corpus.

The multidrug resistance-associated protein 2 (MRP2, ABCC2), mediates the efflux of several conjugated compounds across the apical membrane of the hepatocyte into the bile canaliculi. We identified MRP2 in a screen designed to isolate genes that are regulated by the farnesoid X-activated receptor (FXR, NR1H4). MRP2 mRNA levels were induced following treatment of human or rat hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands. In addition, we have shown that MRP2 expression is regulated by the pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3). Thus, treatment of rodent hepatocytes with PXR or CAR agonists results in a robust induction of MRP2 mRNA levels. The dexamethasone- and pregnenolone 16α-carbonitrile-dependent induction of MRP2expression was not evident in hepatocytes derived from PXR null mice. In contrast, induction of MRP2 by phenobarbital, an activator of CAR, was comparable in wild-type and PXR null mice. An unusual 26-bp sequence was identified 440 bp upstream of theMRP2 transcription initiation site that contains an everted repeat of the AGTTCA hexad separated by 8 nucleotides (ER-8). PXR, CAR, and FXR bound with high affinity to this element as heterodimers with the retinoid X receptor α (RXRα, NR2B1). Luciferase reporter gene constructs containing 1 kb of the rat MRP2 promoter were prepared and transiently transfected into HepG2 cells. Luciferase activity was induced in a PXR-, CAR-, or FXR-dependent manner. Furthermore, the isolated ER-8 element was capable of conferring PXR, CAR, and FXR responsiveness on a heterologous thymidine kinase promoter. Mutation of the ER-8 element abolished the nuclear receptor response. These studies demonstrate that MRP2 is regulated by three distinct nuclear receptor signaling pathways that converge on a common response element in the 5′-flanking region of this gene.

Subfields: Genetics, Oncology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/9be7be35fbbf1df195f859eb14f46a47c85f121d

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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Mathieu Vinken

In Oncology

1. Christoph Borner
2. A. Moser
3. Min-Sun Kim
4. C. Grunfeld
5. W. Khovidhunkit
6. R. Memon
7. C. Klaassen
8. J. Shigenaga

In Pharmacology

1. B. Goodwin
2. S. Kliewer

Citations in the corpus

• Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. (2002, background): “Expression of MRP2, a basolateral protein that transports glutathione and sulfate conjugates of xenobiotics and various natural com- pounds, was modestly increased in the small intestine of PCN-treated mice and the liver of TCPOBOP-treated mice (Table 3, line 16).”
• Induction of phase I, II and III drug metabolism/transport by xenobiotics (2005, background): “FXR, PXR and CAR appear to be responsible for induction of Mrp2/MRP2 mRNA in rat, mouse and human hepatocytes (Kast et al., 2002).”
• Role of bile acids and bile acid receptors in metabolic regulation. (2009, background): “The ABC transporters MDR3/ABCB4 and MRP2/ABCC2, responsible for hepatobiliary transport of phospholipids and of hydrophilic organic anions like divalent BA conjugates, respectively, are also upregulated by FXR (120, 145).”
• Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, positive): “Furthermore, FXR, PXR and the CAR are able to stimulate Mrp2 expression in rodents via shared binding sites (Kast et al. 2002).”
• Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. (2003, background): “, and multidrug resistance-associated protein 2 (MRP2; ABCC2; Kast et al. 2002).”
• Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation (2010, result): “22) (Kast et al., 2002; Jigorel et al., 2006; Olinga et al., 2008; Richert et al., 2009).”
• Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. (2004, positive): “Specifically, FXR activation increases BSEP expression (230), FXR, PXR, and CAR activation increase MRP2 expression (231), LXR activation increases ABCG5 and”