Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter

1999 ◽  
Vol 277 (6) ◽  
pp. F832-F840 ◽  
Author(s):  
Michel Demeule ◽  
Mathieu Brossard ◽  
Richard Béliveau
Keyword(s):  
Chemotherapeutic Agent ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Rat Tissues ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Anion Transporter ◽  
Renal Brush Border Membranes ◽  
Renal Expression ◽  
Renal Brush Border

The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200–300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.

scholarly journals Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 682-691 ◽  
Author(s):  
J. Craig Hartman ◽  
Kenneth Brouwer ◽  
Arun Mandagere ◽  
Lawrence Melvin ◽  
Richard Gorczynski
Keyword(s):  
Organic Anion ◽  
Hepatic Uptake ◽  
Organic Anion Transporter ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Transport Activity ◽  
Receptor Antagonists ◽  
P Glycoprotein ◽  
Anion Transporter ◽  
Hepatic Transporters

To evaluate potential mechanisms of clinical hepatotoxicity, 4 endothelin receptor antagonists (ERAs) were examined for substrate activity and inhibition of hepatic uptake and efflux transporters in sandwich-cultured human hepatocytes. The 4 transporters studied were sodium-dependent taurocholate cotransporter (NTCP), organic anion transporter (OATP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2). ERA transporter inhibition was examined using the substrates taurocholate (for NTCP and BSEP), [3H]estradiol-17β-d-glucuronide (for OATP), and [2-d-penicillamine, 5-d-penicillamine]enkephalin (for MRP2). ERA substrate activity was evaluated using probe inhibitors ritonavir (OATP and BSEP), bromosulfalein (OATP), erythromycin (P-glycoprotein), probenecid (MRP2 and OATP), and cyclosporin (NTCP). ERAs were tested at 2, 20, and 100 µmol·L–1 for inhibition and at 2 µmol·L–1 as substrates. OATP, NTCP, or BSEP transport activity was not reduced by ambrisentan or darusentan. Bosentan and sitaxsentan attenuated NTCP transport at higher concentrations. Only sitaxsentan decreased OATP transport (52%), and only bosentan reduced BSEP transport (78%). MRP2 transport activity was unaltered. OATP inhibitors decreased influx of all ERAs. Darusentan influx was least affected (84%–100% of control), whereas bosentan was most affected (32%–58% of control). NTCP did not contribute to influx of ERAs. Only bosentan and darusentan were shown as substrates for both BSEP and P-glycoprotein efflux. All ERAs tested were substrates for at least one hepatic transporter. Bosentan and sitaxsentan, but not ambrisentan and darusentan, inhibited human hepatic transporters, which provides a potential mechanism for the increased hepatotoxicity observed for these agents in the clinical setting.

Effect of erythropoietin on mercury-induced nephrotoxicity: Role of membrane transporters

2020 ◽  
pp. 096032712095810
Author(s):  
MH Hazelhoff ◽  
AM Torres
Keyword(s):  
Renal Function ◽  
Organic Anion ◽  
Absorption Spectrometry ◽  
Renal Tissue ◽  
Mercury Content ◽  
Organic Anion Transporter ◽  
Tubular Injury ◽  
Human Erythropoietin ◽  
Anion Transporter ◽  
Renal Expression

Mercury is a widespread pollutant. Mercuric ions uptake into tubular cells is supported by the Organic anion transporter 1 (Oat1) and 3 (Oat3) and its elimination into urine is through the Multidrug resistance-associated protein 2 (Mrp2). We investigated the effect of recombinant human erythropoietin (Epo) on renal function and on renal expression of Oat1, Oat3, and Mrp2 in a model of mercuric chloride (HgCl2)-induced renal damage. Four experimental groups of adult male Wistar rats were used: Control, Epo, HgCl2, and Epo + HgCl2. Epo (3000 IU/kg, b.w., i.p.) was administered 24 h before HgCl2 (4 mg/kg, b.w., i.p.). Experiments were performed 18 h after the HgCl2 dose. Parameters of renal function and structure were evaluated. The protein expression of Oat1, Oat3 and Mrp2 in renal tissue was assessed by immunoblotting techniques. Mercury levels were determined by cold vapor atomic absorption spectrometry. Pretreatment with Epo ameliorated the HgCl2-induced tubular injury as assessed by histopathology and urinary biomarkers. Immunoblotting showed that pretreatment with Epo regulated the renal expression of mercury transporters in a way to decrease mercury content in the kidney. Epo pretreatment ameliorates HgCl2-induced renal tubular injury by modulation of mercury transporters expression in the kidneys.

Probenecid Interacts with the Pharmacokinetics of Morphine-6-glucuronide in Humans

2004 ◽  
Vol 101 (6) ◽  
pp. 1394-1399 ◽  
Author(s):  
Carsten Skarke ◽  
Michael Langer ◽  
Marwan Jarrar ◽  
Helmut Schmidt ◽  
Gerd Geisslinger ◽  
...  
Keyword(s):  
Organic Anion ◽  
Plasma Concentrations ◽  
Organic Anion Transporter ◽  
Laboratory Animals ◽  
Crossover Fashion ◽  
Double Blind ◽  
P Glycoprotein ◽  
Anion Transporter ◽  
Transmembrane Transporters ◽  
Multidrug Resistance Related Protein

Background Evidence obtained from porcine cell cultures and experiments in laboratory animals indicates that transmembrane transporters may play a role in the distribution of the active morphine metabolite morphine-6-glucuronide (M6G). This was evaluated in a study in healthy volunteers. Methods Ten subjects received an intravenous M6G infusion for 30 min at a dosage of 0.5 mg/kg body weight, leading to M6G plasma concentrations approximately two to three times higher than those observed with analgesic morphine doses in subjects with normal kidney function. In a randomized, double-blind, three-way crossover fashion, subjects received 800 mg quinidine for inhibition of P-glycoprotein; 500 mg probenecid for inhibition of other transporters, including organic anion transporter peptide, multidrug resistance-related protein, and organic anion transporter families; or placebo 1 h before the start of M6G administration. Plasma concentrations of M6G and pupil size were measured for 7 h. Results Probenecid pretreatment resulted in a decrease in the clearance of M6G from 8.3 +/- 1 l/h to 6.7 +/- 1.3 l/h (factor of 0.8; P < 0.05 vs. placebo cotreatment). This was paralleled by an increase by a factor of 1.2 of the area under the miotic effect-versus-time curves (P < 0.05 vs. placebo). In contrast, quinidine pretreatment had no influence on the pharmacokinetics of M6G. Conclusions The active morphine metabolite is subject to transmembrane transport by transporters inhibited by probenecid in humans.

Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions

Nephrology ◽  
2017 ◽  
Vol 22 (8) ◽  
pp. 642-648 ◽  
Author(s):  
María Julia Severin ◽  
María Herminia Hazelhoff ◽  
Romina Paula Bulacio ◽  
María Eugenia Mamprin ◽  
Anabel Brandoni ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Renal Expression

Excretory transport of xenobiotics by dogfish shark rectal gland tubules

1998 ◽  
Vol 275 (3) ◽  
pp. R697-R705 ◽  
Author(s):  
David S. Miller ◽  
Rosalinde Masereeuw ◽  
John Henson ◽  
Karl J. Karnaky
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Rectal Gland ◽  
Specific Staining ◽  
Luminal Membrane ◽  
P Glycoprotein ◽  
Anion Transporter ◽  
Dogfish Shark ◽  
Sulforhodamine 101 ◽  
Nacl Excretion

Marine elasmobranch rectal gland is a specialized, osmoregulatory organ composed of numerous blind-ended, branched tubules emptying into a central duct. To date, NaCl excretion has been its only described function. Here we use isolated rectal gland tubule fragments from dogfish shark ( Squalus acanthias), fluorescent xenobiotics, and confocal microscopy to describe a second function, xenobiotic excretion. Isolated rectal gland tubules rapidly transported the fluorescent organic anion sulforhodamine 101 from bath to lumen. Luminal accumulation was concentrative, saturable, and inhibited by cyclosporin A (CSA), chlorodinitrobenzene, leukotriene C4, and KCN. Inhibitors of renal organic anion transport (probenecid, p-aminohippurate), organic cation transport (tetraethylammonium and verapamil), and P-glycoprotein (verapamil) were without effect. Cellular accumulation of sulforhodamine 101 was not concentrative, saturable, or inhibitable. Rectal gland tubules did not secrete fluorescein, daunomycin, or a fluorescent CSA derivative. Finally, frozen rectal gland sections stained with an antibody to a hepatic canalicular multispecific organic anion transporter (cMOAT or MRP2) showed heavy and specific staining on the luminal membrane of the epithelial cells. We conclude that rectal gland is capable of active and specific excretion of xenobiotics and that such transport is mediated by a shark analog of MRP2, an ATP-driven xenobiotic transporter, but not by P-glycoprotein.

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