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ToxSci Advance Access originally published online on February 25, 2007
Toxicological Sciences 2007 97(1):103-110; 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)

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},§,¶,1

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

1 To whom correspondence should be addressed at Department of Physiology, Dartmouth Medical School, North College Street, Hanover, NH 03755. Fax: 603-650-1130. E-mail: bas{at}dartmouth.edu.

Received January 24, 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 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.

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


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