MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus).
We used proximal tubules isolated from the killifish, Fundulus heteroclitus, to examine the effect of environmentally relevant, sublethal levels of arsenic on the function and expression of MRP2, an ABC transporter that transports xenobiotics into urine, including arsenic-glutathione conjugates. Exposure of fish to arsenic as sodium arsenite (4-14 days) increased both MRP2 expression in the apical membrane of proximal tubules and MRP2-mediated transport activity. The level of MRP2 mRNA was not affected, suggesting a posttranslational mechanism of action. Acute exposure of proximal tubules isolated from control fish to 75-375 ppb arsenic decreased mitochondrial function (inner membrane electrical potential). However, in tubules from fish that were preexposed to arsenic (4-14 days), no such effect on mitochondrial function was observed. Thus, chronic in vivo exposure to arsenic induces mechanisms that protect proximal tubules during subsequent arsenic exposure. Upregulation of MRP2 expression and activity is one likely contributing factor.
Miller
David S
DS
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Shaw
Joseph R
JR
Stanton
Caitlin R
CR
Barnaby
Roxanna
R
Karlson
Katherine H
KH
Hamilton
Joshua W
JW
Stanton
Bruce A
BA
D000818:Animals; D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D023781:Fundulidae; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D017670:Sodium Compounds / Q000378:metabolism / Q000633:toxicity*; D014018:Tissue Distribution; D015854:Up-Regulation; D014874:Water Pollutants, Chemical / Q000378:metabolism / Q000633:toxicity*
D018053:Arsenites; D005452:Fluoresceins; D005456:Fluorescent Dyes; D026901:Membrane Transport Proteins; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D017670:Sodium Compounds; D014874:Water Pollutants, Chemical; C103864:fluorescein-methotrexate; C017947:sodium arsenite