The Role of Protein Synthesis and Degradation in the Post-Transcriptional Regulation of Rat Multidrug Resistance-Associated Protein 2 (Mrp2, Abcc2)

Jones, Brett R.; Li, Wei; Cao, Jingsong; Hoffman, Tim; Gerk, Phillip M.; Vore, Mary

doi:10.1124/mol.105.013144

Cited by 44 publications

(36 citation statements)

References 31 publications

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“…siRNAs have already been used to reverse multidrug resistance in human cancer cell lines due to overexpression of P-glycoprotein (19), MRP1 (12), MRP2 (21), MRP4 (31), or BCRP (30). The incomplete decreased expression observed here (about 70%) is in line with what is commonly observed with this type of approach for other transporters (12,21,41) and could be accounted for by the very large amount of protein present (41) and/or its long half-life (as is the case for other transporters, such as P-glycoprotein [26], MRP1 [1], or MRP2 [16]), as well as the short half-life of the siRNAs.…”

Section: Discussionsupporting

confidence: 70%

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Márquez

Caceres

Mingeot‐Leclercq

et al. 2009

Antimicrob Agents Chemother

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Ciprofloxacin, the most widely used totally synthetic antibiotic, is subject to active efflux mediated by a MRP-like transporter in wild-type murine J774 macrophages. To identify the transporter among the seven potential Mrps, we used cells made resistant to ciprofloxacin obtained by long-term exposure to increasing drug concentrations (these cells show less ciprofloxacin accumulation and provide a protected niche for ciprofloxacin-sensitive intracellular Listeria monocytogenes). In the present paper, we first show that ciprofloxacin-resistant cells display a faster efflux of ciprofloxacin which is inhibited by gemfibrozil (an unspecific MRP inhibitor). Elacridar, at a concentration known to inhibit P-glycoprotein and breast cancer resistance protein (

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Section: Discussionsupporting

confidence: 70%

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Márquez

Caceres

Mingeot‐Leclercq

et al. 2009

Antimicrob Agents Chemother

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“…There was a clear parallel between the protein content of Abcc2 and the transport activity, suggesting that cPKC activation induces a decrease in the transport activity of Abcc2 as a result of decreased protein content of Abcc2 on BBM surface. It is reported that the half-life of Abcc2 in the canalicular membrane is as long as 27 h (Jones et al, 2005). If Abcc2 in the BBM fraction is as stable as that in the bile canalicular membrane, the decrease in BBM observed without a change in the total amount of Abcc2 is probably caused by accelerated internalization rather than impaired trafficking of newly synthesized molecules to the BBM.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Apical Localization of Abcc2/Mrp2 and Phosphorylation Status of Ezrin in Rat Intestine

Nakano

Sekine²,

Ito

et al. 2009

Drug Metab Dispos

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ABSTRACT:The multidrug resistance-associated protein 2/ATP-binding cassette transporter family C2 (Mrp2/Abcc2) is an ATP-dependent export pump that mediates the transport of a variety of organic anions. Abcc2 is mainly expressed on the canalicular membrane of hepatocytes and also the brush-border membrane of intestinal epithelial cells. We have previously reported that Abcc2 is rapidly internalized from the canalicular membrane during acute oxidative stress, which induces protein kinase C (PKC) activation in rat liver. However, it has not been elucidated whether PKC is involved in the regulation of Abcc2 localization in other tissues. In this study, we investigated this issue in rat intestinal epithelia. Exposure to thymeleatoxin, a conventional PKC (cPKC) activator, for 20 min reduced the cumulative glutathione S-bimane efflux for 40 min via Abcc2 from 30.3 ؎ 2.1 nmol/cm to 18.1 ؎ 1.6 nmol/cm. Likewise, the Abcc2 expression in the brush-border membrane of the small intestine was reduced to half that of the control without changing the total amount of Abcc2 present in the homogenate. Immunoprecipitation analysis suggested an interaction between Abcc2 and ezrin, a scaffolding protein that is dominantly expressed in the intestine. Thymeleatoxin treatment decreased the amount of the active form (C-terminally phosphorylated form) of ezrin and the amount of Abcc2 that coimmunoprecipitated with ezrin. These results indicate that cPKC activation diminishes the protein-protein interaction between ezrin and Abcc2. In conclusion, the phosphorylation status of ezrin correlates with the cell surface expression of Abcc2 in the rat small intestine, which may be regulated by cPKC.The small intestine is a highly differentiated organ with a barrier function against xenobiotics and a gateway function for nutrients. The ATP-binding cassette (ABC) transporter family, including P-glycoprotein/multidrug resistance protein 1 (P-gp/Mdr1/Abcb1), breast cancer resistant protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2), are well known efflux transporters that are located on the brush-border membrane (BBM) of small intestinal epithelia to limit the absorption of a broad range of compounds (Takano et al., 2006). The distinct but sometimes overlapping substrate specificities of these efflux transporters have been shown previously (Chan et al., 2004). Indeed, a significant increase in the oral absorption of their substrates, including drugs and carcinogens, was confirmed in animals genetically deficient in these transporters (Dietrich et al., 2001;Yamaguchi et al., 2002).Several reports indicated the disparity between mRNA and protein expression of Abcc2 in the intestine. Naud et al. (2007) reported that Abcc2 protein expression was reduced to approximately 40% of that of the control during chronic renal failure in rats, but its mRNA expression was unaffected. Dietrich et al. (2004) also reported ABCC2 protein expression was reduced to approximately 27% of that of the control patients in the human intestine du...

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“…The present data are in accordance with a recent report showing that Mrp2 is not induced by PCN in mouse liver. However, it has been reported that Mrp2 may be regulated in rat liver at a post-translational step (Gerk and Vore, 2002;Johnson and Klaassen, 2002;Jones et al, 2005). Mdr1a is induced in mouse small intestine by PCN, but not in either liver or kidney.…”

Section: Discussionmentioning

confidence: 99%

Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

Cheng¹,

Klaassen²

2006

Drug Metab Dispos

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ABSTRACT:Multiple transporter systems are involved in the disposition of xenobiotics and endogenous compounds. The pregnane X receptor (PXR) is a major chemical sensor known to activate the expression of CYP3A/Cyp3a in humans and rodents. The purpose of this study is to systematically determine whether the major xenobiotic transporters in liver, kidney, duodenum, jejunum, and ileum are induced by pregnenolone-16␣-carbonitrile (PCN), and whether this increase is mediated by the nuclear receptor PXR. In liver, PCN induced the expression of Oatp1a4 and Mrp3 mRNA in wild-type (WT) mouse liver, but not in PXR-null mice. In kidney, PCN did not alter the expression of any drug transporter. In duodenum, PCN increased Abca1 and Mdr1a mRNA expression in WT mice, but not in PXR-null mice. In jejunum and ileum, PCN increased Mdr1a and Mrp2 mRNA, but decreased Cnt2 mRNA in WT mice, but none of these transporters was altered when PCN was administered to PXR-null mice. Therefore, PCN regulates the expression of some transporters, namely, Oatp1a4 and Mrp3 in liver, as well as Abca1, Cnt2, Mdr1a, and Mrp2 in small intestine via a PXR-mediated mechanism.The pregnane X receptor (PXR, NR1I2), also called steroid-xenobiotic receptor or pregnane-activated receptor, is an orphan nuclear receptor first identified by Kliewer and coworkers (Lehmann et al., 1998). PXRs have been characterized in rats, mice, humans, rabbits, and chickens. Mouse PXR shares 95% sequence similarity to rat and 77% to human PXR (Zhang et al., 1999;Moore et al., 2003).PXR is a master regulator of phase I and II metabolism of xenobiotics. Upon ligand binding, PXR forms a heterodimer with the retinoid X receptor ␣ and then transactivates target genes. PXR ligands generally induce Cyp3a/CYP3A genes in rats, mice, and humans (Goodwin et al., 2002;Guo et al., 2002b;Cheng et al., 2005b). One exception is CYP3A41, which is down-regulated by dexamethasone (DEX) in a PXR-dependent manner (Anakk et al., 2004). Pregnenolone-16␣-carbonitrile (PCN) also regulates phase II drug-metabolizing enzymes, such as glutathione S-transferase ␣1 and 1, rat UDP-glucuronosyltransferase 1a1 (Ugt1a1) (Chen et al., 2003), and sulfotransferase 1b1 (Dunn et al., 1999). In addition, PCN induces the expression of some transprters, such as rat Abca1 (Sporstol et al., 2005), human MRP2, and MRP3 (Kretschmer and Baldwin, 2005).The regulation of hepatic and small intestinal gene expression by two potent rat PXR agonists, L-742694 and DEX, has been examined after oral administration to female Sprague-Dawley rats using DNA microarray analysis (Hartley et al., 2004). Both L-742694 and DEX elicited robust increases in gene expression of Cyp3a1/23, Cyp3a18, Ugt1a1, Ugt2b1, and Oatp1a4 in rat liver. However, both L-742694 and DEX suppressed rat Cyp3a1/23, Cyp3a18, Ugt1a1, Ugt2b1, Oatp1a4, and Mrp3 expression in intestine (Hartley et al., 2004). There was a distinct lack of coordinated interorgan expression of genes common to both hepatic and intestinal tissues in rats (Hartley et al., 2004).Mice and rats...

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The Role of Protein Synthesis and Degradation in the Post-Transcriptional Regulation of Rat Multidrug Resistance-Associated Protein 2 (Mrp2, Abcc2)

Cited by 44 publications

References 31 publications

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells

Correlation between Apical Localization of Abcc2/Mrp2 and Phosphorylation Status of Ezrin in Rat Intestine

Regulation of mRNA Expression of Xenobiotic Transporters by the Pregnane X Receptor in Mouse Liver, Kidney, and Intestine

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