scholarly journals Differential expression of multidrug resistance (mdr) and canalicular multispecific organic anion transporter (cMOAT) genes following extrahepatic biliary obstruction in rats

IUBMB Life ◽  
1998 ◽  
Vol 44 (3) ◽  
pp. 443-452
Author(s):  
Tatehiro Kagawa ◽  
Norihito Watanabe ◽  
Masahiro Sato ◽  
Atsushi Nakano ◽  
Yasuhiro Nishizaki ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Differential Expression ◽  
Biliary Obstruction ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Extrahepatic Biliary Obstruction

Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

2013 ◽  
Vol 162 (6) ◽  
pp. 398-409 ◽  
Author(s):  
Azza A.K. El-Sheikh ◽  
Rick Greupink ◽  
Heleen M. Wortelboer ◽  
Jeroen J.M.W. van den Heuvel ◽  
Marieke Schreurs ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Organic Anion ◽  
Immunosuppressive Drugs ◽  
Organic Anion Transporter ◽  
Anion Transporter

scholarly journals Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir

2016 ◽  
Vol 60 (10) ◽  
pp. 6260-6270 ◽  
Author(s):  
Xi Yang ◽  
Zhiyuan Ma ◽  
Sisi Zhou ◽  
Yayun Weng ◽  
Hongmei Lei ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Multiple Drug ◽  
Renal Secretion ◽  
Renal Tubular Cells ◽  
Anion Transporter ◽  
Chronic Hepatitis B Virus ◽  
In Cells

ABSTRACTEntecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.

scholarly journals Direct Evidence that Saquinavir Is Transported by Multidrug Resistance-Associated Protein (MRP1) and Canalicular Multispecific Organic Anion Transporter (MRP2)

2002 ◽  
Vol 46 (11) ◽  
pp. 3456-3462 ◽  
Author(s):  
Gregory C. Williams ◽  
Angela Liu ◽  
Gregory Knipp ◽  
Patrick J. Sinko
Keyword(s):  
Multidrug Resistance ◽  
Cell Lines ◽  
Direct Evidence ◽  
Organic Anion ◽  
Lethal Dose ◽  
Organic Anion Transporter ◽  
Cell Monolayers ◽  
Directed Transport ◽  
Anion Transporter ◽  
Efflux Ratio

ABSTRACT To determine if saquinavir mesylate (saquinavir) is a substrate of human multidrug resistance-associated protein 1 (hMRP1 [ABCC1]) or hMRP2 (cMOAT, or ABCC2), MDCKII cells that overexpress either hMRP1 (MDCKII-MRP1) or hMRP2 (MDCKII-MRP2) were used to investigate saquinavir's cytotoxicity and transport in comparison with those of control MDCKII wild-type (MDCKII/wt) cells. Cytotoxicity was assessed with the mitochondrial marker MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium], and saquinavir transport was measured directly through the cell monolayers. GF120918 (an inhibitor of P glycoprotein, but not of the MRP family) and MK-571 (an MRP family inhibitor) were used to delineate the specific contributions of these transporters to saquinavir cytotoxicity and transport. In the presence of GF120918 and increasing saquinavir concentrations, the MDCKII-MRP1 (50% lethal dose [LD50] = 10.5 μM) and MDCKII-MRP2 (LD50 = 27.1 μM) cell lines exhibited statistically greater viability than the MDCKII/wt cells (LD50 = 7.8 μM). Saquinavir efflux was directional, not saturable, and was inhibited by MK-571 (35 and 75 μM) in all cell lines. The ratios of saquinavir (3 μM) basolateral to apical permeability (i.e., efflux ratios) for the MDCKII/wt, MDCKII-MRP1, and MDCKII-MRP2 cell monolayers were 2.6, 1.8, and 6.8, respectively. The MDCKII-MRP1 cells have a significantly reduced saquinavir efflux ratio relative to MDCKII/wt cells, due to basolaterally directed transport by hMRP1 competing with endogenous, apically directed canine MRP2. The MDCKII-MRP2 cells have a significantly increased saquinavir efflux ratio relative to MDCKII/wt cells, due to the additive effects of the apically directed transport by hMRP2 and endogenous MRP2. Collectively, the cytotoxicity and transport results provide direct evidence that saquinavir is transported by MRP1 and MRP2.

Short-term regulation of multidrug resistance-associated protein 3 in rat and human hepatocytes

2005 ◽  
Vol 288 (6) ◽  
pp. G1252-G1258 ◽  
Author(s):  
Priyamvada Chandra ◽  
Peijin Zhang ◽  
Kim L. R. Brouwer
Keyword(s):  
Multidrug Resistance ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Rat Hepatocytes ◽  
Human Hepatocytes ◽  
Organic Anion Transporter ◽  
Intracellular Camp ◽  
Short Term ◽  
Anion Transporter ◽  
Rat Livers

The short-term regulation of multidrug resistance-associated protein 3 (Mrp3/MRP3) by cAMP and PKC was investigated in sandwich-cultured rat and human hepatocytes and isolated perfused rat livers. The modulator glucagon (500 nM) and the phorbol ester PMA (0.1 μM) were utilized to increase intracellular cAMP and PKC levels, respectively. In glucagon-treated rat hepatocytes, efflux of the Mrp3 substrate 5-(6)-carboxy-2′,7′-dichlorofluorescein (CDF) increased ∼1.5-fold, even in hepatocytes treated with the organic anion transporter (Oatp) inhibitor sulfobromophthalein (BSP). Confocal microscopy revealed more concentrated Mrp3 fluorescence in the basolateral membrane (less diffuse staining pattern) with glucagon treatment. PMA had no effect on Mrp3 activity or localization in sandwich-cultured rat hepatocytes. Glucagon and PMA treatment in isolated perfused rat livers resulted in a threefold increase (14 ± 4.6 μl·min−1·g liver−1) and a fourfold decrease (1.3 ± 0.3 μl·min−1·g liver−1) in CDF basolateral clearance compared with control livers (4.7 ± 2.3 μl·min−1·g liver−1), whereas CDF biliary clearance was not statistically different. In sandwich-cultured human hepatocytes, glucagon treatment resulted in a 1.3-fold increase in CDF efflux and a concomitant increase in MRP3 fluorescence in the basolateral membrane. In summary, cAMP and PKC appear to be involved in the short-term regulation of Mrp3/MRP3, as demonstrated by alterations in activity and localization in rat and human hepatocytes.

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