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ToxSci Advance Access published online on February 25, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm030
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MRP2 and Acquired Tolerance to Inorganic Arsenic in the Kidney of Killifish (Fundulus heteroclitus)

MRP2 AND ACQUIRED TOLERANCE

David S. Miller*,{dagger}, Joseph R. Shaw{dagger},{ddagger},§, Caitlin R. Stanton{dagger},¶, Roxanna Barnaby, Katherine H. Karlson, Joshua W. Hamilton§,|| and Bruce A. Stanton{dagger},§,¶

* Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709 {dagger} Mt. Desert Island Biological Laboratory, Salisbury Cove, ME 04672 {ddagger} Department of Biological Sciences, Dartmouth College, Hanover, NH 03755 § Center for Environmental Health Sciences, Dartmouth Medical School, Hanover NH 03755 Department of Physiology, Dartmouth Medical School, Hanover, NH 03755 || Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755

Corresponding author: Bruce A. Stanton, Ph.D., Department of Physiology, Dartmouth Medical School, N. College St., Hanover, NH 03755, 603-650-1775, FAX 603-650-1130, bas{at}Dartmouth.edu

Email addresses: David S. Miller (miller{at}niehs.nih.gov), Joseph R. Shaw (Joseph.R.Shaw{at}Dartmouth.EDU), Caitlin R. Stanton (caitlin.r.stanton{at}gmail.com), Roxanna Barnaby (Roxanna.L.Barnaby{at}Dartmouth.EDU), Katherine H. Karlson (Katherine.H.Karlson{at}Dartmouth.EDU), Joshua W. Hamilton (Joshua.W.Hamilton{at}Dartmouth.EDU) and Bruce A. Stanton (bas{at}Dartmouth.edu)

Received January 24, 2007; revision received February 18, 2007; accepted February 19, 2007


  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 pre-exposed 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. Up-regulation of MRP2 expression and activity is one likely contributing factor.

Key Words: Adaptation; xenobiotic transport; Abcc2; environmental toxicant.


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