MDR1 transporter protects against paraquat-induced toxicity in human and mouse proximal tubule cells.

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.

[1]  Ji-hong Pan,et al.  MDR1 Single Nucleotide Polymorphism G2677T/A and Haplotype Are Correlated with Response to Docetaxel-Cisplatin Chemotherapy in Patients with Non-Small-Cell Lung Cancer , 2008, Respiration.

[2]  E. Richfield,et al.  Quantification of Paraquat, MPTP, and MPP+ in brain tissue using microwave-assisted solvent extraction (MASE) and high-performance liquid chromatography–mass spectrometry , 2009, Analytical and bioanalytical chemistry.

[3]  Shuzhong Zhang,et al.  Transport of Paraquat by Human Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Family , 2007, Journal of Pharmacology and Experimental Therapeutics.

[4]  C. Gibson,et al.  Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia , 2012, Journal of Pharmacology and Experimental Therapeutics.

[5]  J. Duarte,et al.  P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity. , 2006, Free radical biology & medicine.

[6]  T. Shibasaki,et al.  Relationship between expression of drug-resistance factors and drug sensitivity in normal human renal proximal tubular epithelial cells in comparison with renal cell carcinoma. , 2005, Oncology reports.

[7]  Hongbing Wang,et al.  Deficiency of Multidrug and Toxin Extrusion 1 Enhances Renal Accumulation of Paraquat and Deteriorates Kidney Injury in Mice , 2011, Molecular pharmaceutics.

[8]  D. Youssef,et al.  Multi-drug resistance-1 gene polymorphisms in nephrotic syndrome: impact on susceptibility and response to steroids. , 2013, Gene.

[9]  R. Robey,et al.  Assessment of Drug Transporter Function Using Fluorescent Cell Imaging , 2013, Current protocols in toxicology.

[10]  K. Bircsak,et al.  Inhibition of Human MDR1 and BCRP Transporter ATPase Activity by Organochlorine and Pyrethroid Insecticides , 2013, Journal of biochemical and molecular toxicology.

[11]  G. Duggin,et al.  The renal excretory mechanisms and the role of organic cations in modulating the renal handling of paraquat. , 1998, Pharmacology & therapeutics.

[12]  J. Duarte,et al.  Paraquat Poisonings: Mechanisms of Lung Toxicity, Clinical Features, and Treatment , 2008, Critical reviews in toxicology.

[13]  Xingguo Cheng,et al.  Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a, Mdr1b, Mdr2) in Mice , 2009, Drug Metabolism and Disposition.

[14]  Oehme Fw,et al.  A literature review of paraquat toxicity. , 1984 .

[15]  Kent D. Sugden,et al.  Absence of P-Glycoprotein Transport in the Pharmacokinetics and Toxicity of the Herbicide Paraquat , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[16]  E. Felip,et al.  Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine. , 2011, Lung cancer.

[17]  N. Buckley,et al.  Medical management of paraquat ingestion. , 2011, British journal of clinical pharmacology.

[18]  J. Manautou,et al.  Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice. , 1998, Toxicology.

[19]  Y. Hayashizaki,et al.  Emerging new technologies in Pharmacogenomics: rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1). , 2010, Pharmacology & therapeutics.

[20]  P. Kwok,et al.  Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function , 2009, The Pharmacogenomics Journal.