title: Transgenic expression of the human MRP2 transporter reduces cisplatin accumulation and nephrotoxicity in Mrp2-null mice.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Xia
authors.initials: X
authors.lastname: Wen
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCandlish
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
authors.forename: Samira
authors.initials: S
authors.lastname: Syed
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pelis
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut.
authors.forename: José E
authors.initials: JE
authors.lastname: Manautou
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey. Electronic address: aleksunes@eohsi.rutgers.edu.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008822:Mice, Transgenic; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000378:metabolism*; D010984:Platinum / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D061987:Sf9 Cells
chemical_list: D015415:Biomarkers; D002945:Cisplatin; D005978:Glutathione; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010984:Platinum; C000715087:ABCC2 protein, human