Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family.
Paraquat (N,N-dimethyl-4-4'-bipiridinium; PQ), a widely used herbicide, when ingested accidentally or intentionally can cause major organ toxicities in lung, liver, and kidney. Because PQ is primarily eliminated in the kidney, renal elimination, including tubular transport, plays a critical role in controlling systemic exposure to the herbicide. The goal of this study was to determine the molecular identities of the transporters involved in the renal elimination of PQ. Using stably transfected human embryonic kidney (HEK)-293 cells, we examined the role of human organic cation transporters (hOCTs, SLC22A1-3) and human multidrug and toxic compound extrusion (hMATE)1 in the cellular accumulation and cytotoxicity of PQ. We found that overexpression of hOCT2 but not hOCT1 and hOCT3 in HEK-293 cells significantly enhanced the accumulation and cytotoxicity of PQ (-fold increase for uptake was 12 +/- 0.5, p < 0.01; -fold increase of cytotoxicity was 18 +/- 1.5, p < 0.001). The kinetics of PQ transport was altered in cells expressing a genetic polymorphism of hOCT2 (A270S) in comparison with those expressing the reference hOCT2. In addition, the cellular accumulation and cytotoxicity of PQ were also enhanced in cells expressing hMATE1 (-fold increase for uptake was 18 +/- 3.7, p < 0.0001; -fold increase of cytotoxicity was 5.7 +/- 0.5, p < 0.0001). These results suggest that hOCT2 and hMATE1 mediate PQ transport. These transporters may play an important role in the accumulation and renal excretion of PQ, and they may serve as molecular targets for the prevention and treatment of PQ-induced nephrotoxicity.
Chen
Ying
Y
Department of Biopharmaceutical Sciences, University of California, San Francisco, 1550 4th St., San Francisco, CA 94158, USA.
Zhang
Shuzhong
S
Sorani
Marco
M
Giacomini
Kathleen M
KM
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005021:Ethylamines / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010269:Paraquat / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D014162:Transfection; D000099254:Organic Cation Transporter 3
D017920:Antiporters; D005021:Ethylamines; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D010269:Paraquat; D000644:Quaternary Ammonium Compounds; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C515734:Slc47a1 protein, rat; C052377:tetrapropylammonium; C009405:tetrabutylammonium; C027917:tetramethylammonium; C016162:triethylamine