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Research ArticleArticle

Altered Arsenic Disposition in Experimental Nonalcoholic Fatty Liver Disease

Mark J. Canet, Rhiannon N. Hardwick, April D. Lake, Michael J. Kopplin, George L. Scheffer, Walter T. Klimecki, A. Jay Gandolfi and Nathan J. Cherrington
Drug Metabolism and Disposition September 2012, 40 (9) 1817-1824; DOI: https://doi.org/10.1124/dmd.112.046177
Mark J. Canet
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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Rhiannon N. Hardwick
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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April D. Lake
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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Michael J. Kopplin
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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George L. Scheffer
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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Walter T. Klimecki
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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A. Jay Gandolfi
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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Nathan J. Cherrington
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., R.N.H., A.D.L., M.J.K., W.T.K., A.J.G., N.J.C.); and Department of Pathology, VU Medical Center, Amsterdam, The Netherlands (G.L.S.)
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES006694]; the National Institutes of Health National Institute of Allergy and Infectious Diseases Extramural Activities [Grant AI083927]; the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD062489]; the National Institutes of Health National Institute of Environmental Health Sciences Superfund Research Program [Grant ES04940]; and the National Science Foundation of Arizona Fellowship Program.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.046177.

  • ABBREVIATIONS:

    NAFLD
    nonalcoholic fatty liver disease
    NASH
    nonalcoholic steatohepatitis
    MMA
    monomethyl-arsenic
    DMA
    dimethyl arsenic
    As3mt
    arsenic (3+ oxidation state) methyltransferase
    HPLC
    high-performance liquid chromatography
    MCD
    methionine and choline deficient
    Mrp
    multidrug resistance-associated protein
    Erk
    extracellular signal-regulated kinase
    iAs
    inorganic arsenic
    SAM
    (S)-adenosylmethionine.

  • Received April 9, 2012.
  • Accepted June 14, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (9)
Drug Metabolism and Disposition
Vol. 40, Issue 9
1 Sep 2012
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Research ArticleArticle

ALTERED ARSENIC DISPOSITION IN NAFLD

Mark J. Canet, Rhiannon N. Hardwick, April D. Lake, Michael J. Kopplin, George L. Scheffer, Walter T. Klimecki, A. Jay Gandolfi and Nathan J. Cherrington
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1817-1824; DOI: https://doi.org/10.1124/dmd.112.046177

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Research ArticleArticle

ALTERED ARSENIC DISPOSITION IN NAFLD

Mark J. Canet, Rhiannon N. Hardwick, April D. Lake, Michael J. Kopplin, George L. Scheffer, Walter T. Klimecki, A. Jay Gandolfi and Nathan J. Cherrington
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1817-1824; DOI: https://doi.org/10.1124/dmd.112.046177
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