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Research ArticleArticle

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Rhiannon N. Hardwick, Daniel W. Ferreira, Vijay R. More, April D. Lake, Zhenqiang Lu, Jose E. Manautou, Angela L. Slitt and Nathan J. Cherrington
Drug Metabolism and Disposition March 2013, 41 (3) 554-561; DOI: https://doi.org/10.1124/dmd.112.048439
Rhiannon N. Hardwick
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Daniel W. Ferreira
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Vijay R. More
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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April D. Lake
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Zhenqiang Lu
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Jose E. Manautou
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Angela L. Slitt
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Nathan J. Cherrington
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (R.N.H., A.D.L., N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (D.W.F., J.E.M.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (V.R.M., A.L.S.); and Statistical Consulting Laboratory, University of Arizona, Tucson, Arizona (Z.L.)
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Abstract

The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3′-phosphoadenosine-5′-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.

Footnotes

  • This research was supported by the National Institutes of Health [Grants DK068039, ES006694, AT002842, and HD062489]; and the Liver Tissue Cell Distribution System was supported by the National Institutes of Health [Contract N01-DK-7-0004/HHSN267200700004C].

  • dx.doi.org/10.1124/dmd.112.048439.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received August 6, 2012.
  • Accepted December 7, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

UGT and SULT Enzyme Expression in Human NAFLD

Rhiannon N. Hardwick, Daniel W. Ferreira, Vijay R. More, April D. Lake, Zhenqiang Lu, Jose E. Manautou, Angela L. Slitt and Nathan J. Cherrington
Drug Metabolism and Disposition March 1, 2013, 41 (3) 554-561; DOI: https://doi.org/10.1124/dmd.112.048439

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Research ArticleArticle

UGT and SULT Enzyme Expression in Human NAFLD

Rhiannon N. Hardwick, Daniel W. Ferreira, Vijay R. More, April D. Lake, Zhenqiang Lu, Jose E. Manautou, Angela L. Slitt and Nathan J. Cherrington
Drug Metabolism and Disposition March 1, 2013, 41 (3) 554-561; DOI: https://doi.org/10.1124/dmd.112.048439
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