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Research ArticleMetabolism, Transport, and Pharmacogenomics

Regulation of UDP-Glucuronosyltransferase 1A1 Expression and Activity by MicroRNA 491-3p

Douglas F. Dluzen, Dongxiao Sun, Anna C. Salzberg, Nate Jones, Ryan T. Bushey, Gavin P. Robertson and Philip Lazarus
Journal of Pharmacology and Experimental Therapeutics March 2014, 348 (3) 465-477; DOI: https://doi.org/10.1124/jpet.113.210658
Douglas F. Dluzen
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Dongxiao Sun
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Anna C. Salzberg
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Nate Jones
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Ryan T. Bushey
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Gavin P. Robertson
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Philip Lazarus
Departments of Pharmacology (D.F.D., D.S., N.J., R.T.B., G.P.R., P.L.) and Public Health Sciences (A.C.S.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington (P.L.)
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Abstract

The UDP-glucuronosyltransferase (UGT) 1A enzymes are involved in the phase II metabolism of many important endogenous and exogenous compounds. The nine UGT1A isoforms exhibit high interindividual differences in expression, but their epigenetic regulation is not well understood. The purpose of the present study was to examine microRNA (miRNA) regulation of hepatic UGT1A enzymes and determine whether or not that regulation impacts enzymatic activity. In silico analysis identified miRNA 491-3p (miR-491-3p) as a potential regulator of the UGT1A gene family via binding to the shared UGT1A 3′-untranslated region common to all UGT1A enzymes. Transfection of miR-491-3p mimic into HuH-7 cells significantly repressed UGT1A1 (P < 0.001), UGT1A3 (P < 0.05), and UGT1A6 (P < 0.05) mRNA levels. For UGT1A1, this repression correlated with significantly reduced metabolism of raloxifene into raloxifene-6-glucuronide (ral-6-gluc; P < 0.01) and raloxifene-4′-glucuronide (ral-4′-gluc; P < 0.01). In HuH-7 cells with repressed miR-491-3p expression, there was a significant increase (∼80%; P < 0.01) in UGT1A1 mRNA and a corresponding increase in glucuronidation of raloxifene into ral-6-gluc (50%; P < 0.05) and ral-4′-gluc (22%; P < 0.01). Knockdown of endogenous miR-491-3p in HepG2 cells did not significantly alter UGT1A1 mRNA levels but did increase the formation of ral-6-gluc (50%; P < 0.05) and ral-4′-gluc (34%; P < 0.001). A significant inverse correlation between miR-491-3p expression and both UGT1A3 (P < 0.05) and UGT1A6 (P < 0.01) mRNA levels was observed in a panel of normal human liver specimens, with a significant (P < 0.05) increase in UGT1A3 and UGT1A6 mRNA levels observed in miR-491-3p nonexpressing versus expressing liver specimens. These results suggest that miR-491-3p is an important factor in regulating the expression of UGT1A enzymes in vivo.

Footnotes

    • Received October 18, 2013.
    • Accepted January 3, 2014.
  • This work was funded in part by a student fellowship provided by AstraZeneca (to D.F.D.); grants from the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant R01-DE13158] (to P.L.); the Pennsylvania Department of Health, Health Research Formula Funding Program [Grant 4100038714] (to P.L.); and the National Institutes of Health National Center for Research Resources and National Center for Advancing Translational Sciences [Grant UL1-TR000127].

  • dx.doi.org/10.1124/jpet.113.210658.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 3
1 Mar 2014
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Regulation of UGT1A1 Expression and Activity by miR-491-3p

Douglas F. Dluzen, Dongxiao Sun, Anna C. Salzberg, Nate Jones, Ryan T. Bushey, Gavin P. Robertson and Philip Lazarus
Journal of Pharmacology and Experimental Therapeutics March 1, 2014, 348 (3) 465-477; DOI: https://doi.org/10.1124/jpet.113.210658

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Regulation of UGT1A1 Expression and Activity by miR-491-3p

Douglas F. Dluzen, Dongxiao Sun, Anna C. Salzberg, Nate Jones, Ryan T. Bushey, Gavin P. Robertson and Philip Lazarus
Journal of Pharmacology and Experimental Therapeutics March 1, 2014, 348 (3) 465-477; DOI: https://doi.org/10.1124/jpet.113.210658
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