title: MDR1 transporter protects against paraquat-induced toxicity in human and mouse proximal tubule cells.
abstract: Paraquat is a herbicide that is highly toxic to the lungs and kidneys following acute exposures. Prior studies have demonstrated that the organic cation transporter 2 and multidrug and toxin extrusion protein 1 contribute to the urinary secretion of paraquat in the kidneys. The purpose of this study was to determine whether the multidrug resistance protein 1 (MDR1/Mdr1, ABCB1, or P-glycoprotein) also participates in the removal of paraquat from the kidneys and protects against renal injury. Paraquat transport and toxicity were quantified in human renal proximal tubule epithelial cells (RPTEC) that endogenously express MDR1, HEK293 cells overexpressing MDR1, and Mdr1a/1b knockout mice. In RPTEC cells, reduction of MDR1 activity using the antagonist PSC833 or siRNA transfection increased the cellular accumulation of paraquat by 50%. Reduced efflux of paraquat corresponded with enhanced cytotoxicity in PSC833-treated cells. Likewise, stable overexpression of the human MDR1 gene in HEK293 cells reduced intracellular levels of paraquat by 50%. In vivo studies assessed the renal accumulation and subsequent nephrotoxicity of paraquat (10 or 30 mg/kg ip) in wild-type and Mdr1a/1b knockout mice. At 4 h after paraquat treatment, renal concentrations of paraquat in the kidneys of Mdr1a/1b knockout mice were 750% higher than wild-type mice. By 72 h, paraquat-treated Mdr1a/1b knockout mice had more extensive tubular degeneration and significantly greater mRNA expression of kidney injury-responsive genes, including kidney injury molecule-1, lipocalin-2, and NAD(P)H quinone oxidoreductase 1, compared with wild-type mice. In conclusion, MDR1/Mdr1 participates in the elimination of paraquat from the kidneys and protects against subsequent toxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854.
authors.forename: Xia
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854 Joint Graduate Program in Toxicology, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gibson
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Ill
authors.initials: I
authors.lastname: Yang
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.affiliation: Office of Translational Science, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08854 Department of Environmental and Occupational Medicine, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854 Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey 08854 aleksunes@eohsi.rutgers.edu.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006540:Herbicides / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010269:Paraquat / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D065667:Renal Elimination / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003524:Cyclosporins; D006540:Herbicides; D010269:Paraquat; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C095122:multidrug resistance protein 3; C070272:valspodar
keywords: ABCB1; MDR1; Mdr1a; P-glycoprotein; paraquat; proximal tubule