March 20, 2014Open Access

Transgenic Expression of the Human MRP2 Transporter Reduces Cisplatin Accumulation and Nephrotoxicity in Mrp2-Null Mice

WXWen XiaRutgers, The State University of New Jersey BBBrian BuckleyEnvironmental and Occupational Health Sciences Institute EMElizabeth McCandlishRutgers, The State University of New Jersey

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Abstract

The chemotherapeutic drug cisplatin is actively transported into proximal tubules, leading to acute renal injury. Previous studies suggest that the multidrug resistance–associated protein 2 (Mrp2) transporter may efflux cisplatin conjugates from cells. We sought to determine whether the absence of Mrp2 alters the accumulation and toxicity of platinum in the kidneys of mice and whether transgenic expression of the human MRP2 gene could protect against cisplatin injury in vivo. Plasma, kidneys, and livers from vehicle- and cisplatin-treated wild-type and Mrp2-null mice were collected for quantification of platinum and toxicity. By 24 hours, twofold higher concentrations of platinum were detected in the kidneys and livers of Mrp2-null mice compared with wild types. Enhanced platinum concentrations in Mrp2-null mice were observed in DNA and cytosolic fractions of the kidneys. Four days after cisplatin treatment, more extensive proximal tubule injury was observed in Mrp2-null mice compared with wild-type mice. Kidneys from naive Mrp2-null mice had elevated glutathione S-transferase mRNA levels, which could increase the formation of cisplatin-glutathione conjugates that may be metabolized to toxic thiol intermediates. Transgenic expression of the human MRP2 gene in Mrp2-null mice reduced the accumulation and nephrotoxicity of cisplatin to levels observed in wild-type mice. These data suggest that deficiency in Mrp2 lowers platinum excretion and increases susceptibility to kidney injury, which can be rescued by the human MRP2 ortholog. The chemotherapeutic drug cisplatin is actively transported into proximal tubules, leading to acute renal injury. Previous studies suggest that the multidrug resistance–associated protein 2 (Mrp2) transporter may efflux cisplatin conjugates from cells. We sought to determine whether the absence of Mrp2 alters the accumulation and toxicity of platinum in the kidneys of mice and whether transgenic expression of the human MRP2 gene could protect against cisplatin injury in vivo. Plasma, kidneys, and livers from vehicle- and cisplatin-treated wild-type and Mrp2-null mice were collected for quantification of platinum and toxicity. By 24 hours, twofold higher concentrations of platinum were detected in the kidneys and livers of Mrp2-null mice compared with wild types. Enhanced platinum concentrations in Mrp2-null mice were observed in DNA and cytosolic fractions of the kidneys. Four days after cisplatin treatment, more extensive proximal tubule injury was observed in Mrp2-null mice compared with wild-type mice. Kidneys from naive Mrp2-null mice had elevated glutathione S-transferase mRNA levels, which could increase the formation of cisplatin-glutathione conjugates that may be metabolized to toxic thiol intermediates. Transgenic expression of the human MRP2 gene in Mrp2-null mice reduced the accumulation and nephrotoxicity of cisplatin to levels observed in wild-type mice. These data suggest that deficiency in Mrp2 lowers platinum excretion and increases susceptibility to kidney injury, which can be rescued by the human MRP2 ortholog. Cisplatin is commonly used in chemotherapy regimens for the treatment of solid cancers. The success of cisplatin therapy is limited, in part, by kidney injury. Up to 37% of patients develop signs of nephrotoxicity after receiving a single dose of cisplatin despite strategies such as hydration to limit renal exposure.1Shord S.S. Thompson D.M. Krempl G.A. Hanigan M.H. Effect of concurrent medications on cisplatin-induced nephrotoxicity in patients with head and neck cancer.Anticancer Drugs. 2006; 17: 207-215Crossref PubMed Scopus (49) Google Scholar This is problematic for patients because kidney injury can delay further treatment and limit the total number of chemotherapy cycles received, thereby reducing the overall efficacy of cisplatin-containing regimens. Previous studies have identified the contribution of uptake and efflux transporters to the renal secretion of cisplatin. The organic cation transporter 2 (Oct2; gene Slc22a2) is highly expressed in the kidneys and mediates the renal uptake of cisplatin.2Ciarimboli G. Ludwig T. Lang D. Pavenstadt H. Koepsell H. Piechota H.J. Haier J. Jaehde U. Zisowsky J. Schlatter E. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2.Am J Pathol. 2005; 167: 1477-1484Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 3Ciarimboli G. Deuster D. Knief A. Sperling M. Holtkamp M. Edemir B. Pavenstadt H. Lanvers-Kaminsky C. am Zehnhoff-Dinnesen A. Schinkel A.H. Koepsell H. Jurgens H. Schlatter E. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions.Am J Pathol. 2010; 176: 1169-1180Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 4Burger H. Zoumaro-Djayoon A. Boersma A.W. Helleman J. Berns E.M. Mathijssen R.H. Loos W.J. Wiemer E.A. Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2).Br J Pharmacol. 2010; 159: 898-908Crossref PubMed Scopus (103) Google Scholar, 5Filipski K.K. Loos W.J. Verweij J. Sparreboom A. Interaction of cisplatin with the human organic cation transporter 2.Clin Cancer Res. 2008; 14: 3875-3880Crossref PubMed Scopus (132) Google Scholar Transgenic mice lacking Oct1 and Oct2 transporters exhibit decreased platinum (Pt) excretion and reduced nephrotoxicity.6Filipski K.K. Mathijssen R.H. Mikkelsen T.S. Schinkel A.H. Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.Clin Pharmacol Ther. 2009; 86: 396-402Crossref PubMed Scopus (312) Google Scholar In addition, patients with cancer with a loss-of-function polymorphism in OCT2 (808G>T) are protected against cisplatin renal injury.6Filipski K.K. Mathijssen R.H. Mikkelsen T.S. Schinkel A.H. Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.Clin Pharmacol Ther. 2009; 86: 396-402Crossref PubMed Scopus (312) Google Scholar, 7Iwata K. Aizawa K. Kamitsu S. Jingami S. Fukunaga E. Yoshida M. Yoshimura M. Hamada A. Saito H. Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events.Clin Exp Nephrol. 2012; 16: 843-851Crossref PubMed Scopus (81) Google Scholar Additional data suggest that the copper transporter 1 (Ctr1; gene Slc31a1) participates in the renal uptake of cisplatin,8Pabla N. Murphy R.F. Liu K. Dong Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity.Am J Physiol Renal Physiol. 2009; 296: F505-F511Crossref PubMed Scopus (192) Google Scholar, 9Larson C.A. Blair B.G. Safaei R. Howell S.B. The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs.Mol Pharmacol. 2009; 75: 324-330Crossref PubMed Scopus (141) Google Scholar, 10Chen H.H. Kuo M.T. Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy.Met Based Drugs. 2010; 2010: 1-7Crossref Scopus (191) Google Scholar, 11Lin X. Okuda T. Holzer A. Howell S.B. The copper transporter CTR1 regulates cisplatin uptake in Saccharomyces cerevisiae.Mol Pharmacol. 2002; 62: 1154-1159Crossref PubMed Scopus (204) Google Scholar, 12Ishida S. Lee J. Thiele D.J. Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals.Proc Natl Acad Sci U S A. 2002; 99: 14298-14302Crossref PubMed Scopus (728) Google Scholar although recent work has found conflicting results.13Ivy K.D. Kaplan J.H. A re-evaluation of the role of hCTR1, the human high-affinity copper transporter, in platinum-drug entry into human cells.Mol Pharmacol. 2013; 83: 1237-1246Crossref PubMed Scopus (71) Google Scholar After uptake of cisplatin by Oct2 or Ctr1, the subsequent efflux of cisplatin into the renal lumen is mediated by the multidrug and toxin extrusion protein 1 (Mate1; gene Slc47a1).14Nakamura T. Yonezawa A. Hashimoto S. Katsura T. Inui K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity.Biochem Pharmacol. 2010; 80: 1762-1767Crossref PubMed Scopus (166) Google Scholar As expected, Mate1 knockout mice have increased renal concentrations of cisplatin and enhanced nephrotoxicity.14Nakamura T. Yonezawa A. Hashimoto S. Katsura T. Inui K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity.Biochem Pharmacol. 2010; 80: 1762-1767Crossref PubMed Scopus (166) Google Scholar Once inside the renal cell, cisplatin is biotransformed by spontaneous hydrolysis to monoaquated and diaquated species. Formation of cisplatin aquated intermediates leads to electrophilic attack of cellular macromolecules, such as DNA and protein. The tripeptide glutathione (GSH) can also bind cisplatin and has been suggested to form a variety of nontoxic cisplatin conjugates, including monoplatinum-monoglutathione, diplatinum-monoglutathione, and bis-(glutathionato)-platinum.15Ishikawa T. Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells: molecular characterization of glutathione-platinum complex and its biological significance.J Biol Chem. 1993; 268: 20116-20125Abstract Full Text PDF PubMed Google Scholar, 16Townsend D.M. Marto J.A. Deng M. Macdonald T.J. Hanigan M.H. High pressure liquid chromatography and mass spectrometry characterization of the nephrotoxic biotransformation products of Cisplatin.Drug Metab Dispos. 2003; 31: 705-713Crossref PubMed Scopus (37) Google Scholar It has been postulated that these conjugates have the potential for metabolism to reactive thiol intermediates. Previous studies suggest that the multidrug resistance–associated transporter 2 (Mrp2; gene Abcc2) can efflux GSH conjugates of cisplatin from cancer cells and confer resistance to cytotoxicity.15Ishikawa T. Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells: molecular characterization of glutathione-platinum complex and its biological significance.J Biol Chem. 1993; 268: 20116-20125Abstract Full Text PDF PubMed Google Scholar, 17Cui Y. Konig J. Buchholz J.K. Spring H. Leier I. Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.Mol Pharmacol. 1999; 55: 929-937PubMed Google Scholar, 18Kawabe T. Chen Z.S. Wada M. Uchiumi T. Ono M. Akiyama S. Kuwano M. Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2).FEBS Lett. 1999; 456: 327-331Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Overexpression of human (h)MRP2 increases cisplatin resistance by 10-fold in human embryonic kidney cells17Cui Y. Konig J. Buchholz J.K. Spring H. Leier I. Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.Mol Pharmacol. 1999; 55: 929-937PubMed Google Scholar and reduces cisplatin accumulation by 30% in porcine kidney LLC-PK1 cells.18Kawabe T. Chen Z.S. Wada M. Uchiumi T. Ono M. Akiyama S. Kuwano M. Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2).FEBS Lett. 1999; 456: 327-331Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Moreover, primary hepatocytes isolated from transport-deficient rats (Mrp2-deficient strain) exhibit increased binding of Pt to DNA and enhanced susceptibility to cisplatin cytotoxicity.19Guminski A.D. Balleine R.L. Chiew Y.E. Webster L.R. Tapner M. Farrell G.C. Harnett P.R. Defazio A. MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma.Gynecol Oncol. 2006; 100: 239-246Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar However, the ability of Mrp2 to reduce the accumulation of cisplatin and/or its conjugates and limit renal injury in vivo is not well understood. Therefore, the purpose of this study was to determine whether loss of Mrp2 function enhances renal Pt accumulation and nephrotoxicity in mice and to evaluate the ability of the human MRP2 gene to rescue Mrp2-null mice from heightened cisplatin-induced nephrotoxicity in vivo. Unless otherwise specified, all chemicals were obtained from Sigma-Aldrich (St. Louis, MO). Inside-out Sf9 insect cell plasma membrane vesicles expressing or were from the ability of cisplatin to transport of vesicles were with 2 and concentrations of cisplatin to in for to the were and with was mice were from Mrp2-null mice were obtained from and were were with the was by the and mice on a were from Cisplatin was in after to of to mice were with of or of cisplatin after The of cisplatin used in this study were to used S.S. Thompson D.M. Krempl G.A. Hanigan M.H. Effect of concurrent medications on cisplatin-induced nephrotoxicity in patients with head and neck cancer.Anticancer Drugs. 2006; 17: 207-215Crossref PubMed Scopus (49) Google Scholar was after cisplatin and plasma were collected 1 to days after cisplatin of mice were into metabolism for quantification of Pt concentrations and and from to were in or were and levels were as of renal injury and and concentrations as well as were also GSH was the kidney were with and were for by a a with the the toxicity of agents in PubMed Scopus (37) Google Scholar was isolated The mRNA expression of kidney injury glutathione S-transferase cancer resistance protein and multidrug resistance protein was the DNA of expression of mRNA DNA Metab Dispos. Google Scholar and Ctr1 were by was the and DNA were to 1 of from The and were used for Mate1 and Ctr1 and Oct1 and and protein and was used for the of was in a the were to by with a was to all the to a of by a were in not were with 30% were by plasma mass spectrometry a Pt were for concentrations were This has been used for in R. M. B. A study of the and plasma chromatography to plasma mass Chem. PubMed Scopus Google for or for a is to by was the were and 30% was to the of treatment was used to the was the were and as for a is to by was the were and in the can be in that and are as as The for a is to by was the were and 30% was to the of treatment was used to the in the can be in that and are in a Kidneys were in and were for the of and membrane DNA was isolated the and Kidneys were in was as of and transporters during is on Pharmacol. 2008; PubMed Scopus Google Scholar The were Mrp2 and from Oct2 and Mate1 from and Ctr1 multidrug resistance protein and from was for and were and with or and were a with and a with primary were to not The was used for were with were by or of by the or more data were was for was used to cisplatin as a potential in the of GSH plasma membrane vesicles expressed the Mrp2 and MRP2 with expression of compared with protein The was used for as H. G. N. M. M. M. H. A. of in MRP2 transport J 2012; PubMed Scopus Google Scholar, C. U. A. G. of a for drug with human in membrane J 2010; 75: PubMed Scopus Google Scholar Cisplatin the transport of in plasma membrane vesicles of by was to to to cisplatin. transport was also cisplatin. that concentrations as as have been observed J. M. G. N. Liu G. A study of with cisplatin and in patients with solid with in cell Drugs. PubMed Scopus Google Scholar although is this to tubule Cisplatin renal injury in and Mrp2-null mice levels increased in on By levels in cisplatin-treated Mrp2-null mice were twofold higher in mice. in levels were observed on with a increase in Mrp2-null mice. increases in were also in cisplatin-treated Mrp2-null with detected in mice. Mrp2-null mice in the renal mRNA expression of kidney injury and on compared with mice In addition, Mrp2-null mice had a in and although this was not of kidneys from cisplatin-treated mice proximal tubule and as well as of tubule that was more in Mrp2-null mice days and renal with and were more in Mrp2-null mice. from and Mrp2-null mice of and/or not of Kidneys from and after Cisplatin and after with 2 compared with mice. compared with mice. compared with 2 compared with mice. compared with mice. compared with compared with cisplatin-treated were 2 to days after of cisplatin or and were in and with were for the of and in proximal tubule of renal proximal tubule and by a was as injury of cells with or injury to of injury to of injury to of injury of cells. The number of mice with a is in with are to have kidney injury. The of mice with compared with the total number of mice are as were compared with compared with cisplatin-treated mice. in a Kidneys were 2 to days after of cisplatin or and were in and with were for the of and in proximal tubule of renal proximal tubule and by a was as injury of cells with or injury to of injury to of injury to of injury of cells. The number of mice with a is in with are to have kidney injury. The of mice with compared with the total number of mice are as were concentrations of Pt in Mrp2-null mice were elevated levels 24 and increase in the the to the kidneys, Pt concentrations were higher in the livers of Mrp2-null mice The of Pt from the plasma was and Mrp2-null uptake total Pt excretion into was and in 24 and decreased by and hours, with observed of kidneys from and Mrp2-null mice 24 after cisplatin treatment increases in Pt levels in and DNA not in the membrane in the of cisplatin intermediates and/or can transport the expression of Ctr1, and Mate1 and as well as apical efflux and multidrug resistance protein 1 in of Ctr1, and multidrug resistance protein 1 mRNA and protein was in kidneys from naive and Mrp2-null mice A and of the expression of Oct1 mRNA in Y. and of organic cation transporters in Metab Dispos. 2006; PubMed Scopus Google Scholar mRNA levels of this were also and in Mrp2-null mice mRNA levels were in not mRNA and protein levels were elevated in Mrp2-null to J. D.J. X. J. R. of mice lacking the multidrug resistance protein MRP2 Pharmacol Exp Ther. 2006; PubMed Scopus Google Scholar, K. E. H. J.H. J.H. Schinkel A.H. and anticancer drug transport by Mrp2 in studies Mrp2 knockout Pharmacol Exp Ther. 2006; PubMed Scopus Google Scholar It is whether can transport this increase not to for reduced Pt excretion and enhanced toxicity in Mrp2-null mice. in the mRNA expression of in GSH and were also with expression of and was elevated to in kidneys from naive Mrp2-null mice were in and mRNA levels Renal GSH concentrations were not and Mrp2-null mice mice have been as a transgenic in Mrp2-null N. S. G. and characterization of a MRP2 Metab Dispos. 2012; PubMed Scopus Google Scholar of protein to the membrane of tubules, used against for with the transporter As expected, the Mrp2 detected protein in mice which with on the apical membrane of The MRP2 detected MRP2 protein in that with in the mice. protein was detected in the Mrp2-null mice. of protein into the canalicular membrane of hepatocytes was in mice is a to patients with mice lacking Mrp2 have increased and total J. D.J. X. J. R. of mice lacking the multidrug resistance protein MRP2 Pharmacol Exp Ther. 2006; PubMed Scopus Google Scholar, K. E. H. J.H. J.H. Schinkel A.H. and anticancer drug transport by Mrp2 in studies Mrp2 knockout Pharmacol Exp Ther. 2006; PubMed Scopus Google Scholar We observed in Mrp2-null mice that was reduced in mice that the protein is in the transgenic to of cisplatin to Mrp2-null mice increased and levels as well as kidney injury and mRNA levels to a in mice of MRP2 in mice these to levels observed in mice. Pt levels were higher in the kidneys of Mrp2-null mice compared with and mice in plasma Pt levels were detected concentrations in and mice with cisplatin. Pt concentrations were by plasma mass spectrometry in the kidneys and plasma of and mice 24 after treatment with of cisplatin. are as to and from cisplatin-treated We the role of Mrp2 in the and toxicity of cisplatin in mice. We have enhanced susceptibility of Mrp2-null mice to renal injury by and in toxicity are to higher concentrations of Pt in the kidneys of Mrp2-null mice. It can be suggested that elevated Pt concentrations are to efflux enhanced uptake because levels of Oct2 and Ctr1 mRNA and protein as well as Pt from plasma were The are in to a recent study that that Mrp2 not in the renal excretion and toxicity of cisplatin in J.A. C. Mathijssen R.H. Loos W.J. Sparreboom A. and cisplatin and Pharmacol Ther. 2012; PubMed Scopus Google Scholar This was on and Pt concentrations in cisplatin-treated and Mrp2-null mice that these data are with the because not in renal injury quantification of Pt concentrations in the kidneys and may be a more of in mice. These the of studies for of toxicity these data are with in studies a role for MRP2 in against cisplatin in isolated A.D. Balleine R.L. Chiew Y.E. Webster L.R. Tapner M. Farrell G.C. Harnett P.R. Defazio A. MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma.Gynecol Oncol. 2006; 100: 239-246Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar M. T. T. Y. H. S. 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N. transporter enhances of cisplatin in a head and neck cell cell Lett. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar However, are to the in proximal with GSH is a cisplatin to and is more toxic to LLC-PK1 kidney cells cisplatin D.M. Deng M. Hanigan M.H. of Cisplatin to a in proximal tubule Nephrol. 2003; 14: PubMed Scopus Google Scholar This is further by studies that of and mice from D.M. Hanigan M.H. of or the nephrotoxicity of cisplatin in Pharmacol Exp Ther. 2002; PubMed Scopus Google Scholar, S. H. T. K.D. D.M. of a glutathione against cisplatin kidney 2010; PubMed Scopus Google Scholar and that mice are to cisplatin D.M. Hanigan M.H. of or the nephrotoxicity of cisplatin in Pharmacol Exp Ther. 2002; PubMed Scopus Google Scholar of the role of GSH in the formation of reactive Pt the higher expression of despite GSH levels in Mrp2-null may to the higher susceptibility of these mice to cisplatin toxicity. Therefore, as more for cisplatin conjugates in vivo are be to the cisplatin that are in the of Mrp2-null mice. The protein to the and canalicular and concentrations in Mrp2-null N. S. G. and characterization of a MRP2 Metab Dispos. 2012; PubMed Scopus Google Scholar We have that mice have a susceptibility to cisplatin nephrotoxicity as mice. In and levels were in mice. This may be to the higher MRP2 mRNA in mice compared with N. S. G. and characterization of a MRP2 Metab Dispos. 2012; PubMed Scopus Google Scholar The ability of to protect against the toxicity of has been in on single polymorphism the of to H. E. C. S. J. gene and proximal 2006; PubMed Scopus Google Scholar T.J. Mathijssen R.H. Verweij J. S. Sparreboom A. of the transporter Pharmacol Ther. PubMed Scopus Google Scholar B. M. G. A. A. S. H. M. A. S. M. H. M. M. J. G. and multidrug resistance protein genetic are with 2005; PubMed Scopus Google Scholar and W.J. Lee J.H. J. K. Lee In Lee B. Lee A in is with adverse drug of in patients with 2010; PubMed Google Scholar A that MRP2 not cisplatin and this study was and variants were detected in the study J.A. C. Mathijssen R.H. Loos W.J. Sparreboom A. and cisplatin and Pharmacol Ther. 2012; PubMed Scopus Google Scholar nephrotoxicity was not a polymorphism in the MRP2 gene has been to cisplatin efficacy in patients with cell N. X. Chen B. H. J. Z. MRP2 and and chemotherapy in cell Pharmacol. 2010; PubMed Scopus Google Scholar Based on these further work is to MRP2 in cisplatin efficacy and toxicity. We observed elevated Pt concentrations in the kidneys and livers of Mrp2-null mice compared with mice In the higher Pt concentrations The ability of the kidneys to the Pt in Mrp2-null mice a the may the higher expression of Mate1 mRNA in the X. and of the transporters and toxin extrusion 1 and mRNA expression levels in 2008; 83: PubMed Scopus Google Scholar The of Pt in the livers of Mrp2-null mice not in toxicity. increases in were observed and days in the with or were This in sensitivity to cisplatin may the ability of the kidneys to reactive via metabolism or enhanced in the The data to the the transporters that in the renal and toxicity of cisplatin In the absence of Mrp2 cisplatin-induced nephrotoxicity in mice to elevated concentrations of Pt in the DNA and and to enhanced mRNA Moreover, the MRP2 gene Mrp2-null mice from cisplatin a role for the human in vivo. We for the Mrp2 for and of and for with with and in livers of and mice. was by with protein

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