Title: MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus).
Authors: Miller, David S; Shaw, Joseph R; Stanton, Caitlin R; Barnaby, Roxanna; Karlson, Katherine H; Hamilton, Joshua W; Stanton, Bruce A
Published In Toxicol Sci, (2007 May)
Abstract: 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.
PubMed ID: 17324950
MeSH Terms: Animals; Arsenites/metabolism; Arsenites/toxicity*; Dose-Response Relationship, Drug; Drug Tolerance*; Fluoresceins/metabolism; Fluorescent Dyes/metabolism; Fundulidae*; Kidney Tubules, Proximal/drug effects*; Kidney Tubules, Proximal/metabolism; Membrane Potential, Mitochondrial/drug effects; Membrane Transport Proteins/genetics; Membrane Transport Proteins/metabolism*; Methotrexate/analogs & derivatives; Methotrexate/metabolism; Mitochondria/drug effects; Mitochondria/metabolism; Multidrug Resistance-Associated Proteins/genetics; Multidrug Resistance-Associated Proteins/metabolism*; Protein Processing, Post-Translational/drug effects*; RNA, Messenger/metabolism; Sodium Compounds/metabolism; Sodium Compounds/toxicity*; Tissue Distribution; Up-Regulation; Water Pollutants, Chemical/metabolism; Water Pollutants, Chemical/toxicity*