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Research ArticleArticle

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

Vincent Ménard, Pierre Collin, Guillaume Margaillan and Chantal Guillemette
Drug Metabolism and Disposition December 2013, 41 (12) 2197-2205; DOI: https://doi.org/10.1124/dmd.113.053876
Vincent Ménard
Pharmacogenomics Laboratory, Centre Hospitalier de l’Université Laval de Québec (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada
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Pierre Collin
Pharmacogenomics Laboratory, Centre Hospitalier de l’Université Laval de Québec (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada
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Guillaume Margaillan
Pharmacogenomics Laboratory, Centre Hospitalier de l’Université Laval de Québec (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada
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Chantal Guillemette
Pharmacogenomics Laboratory, Centre Hospitalier de l’Université Laval de Québec (CHU de Québec) Research Center, Faculty of Pharmacy, Laval University, Québec, Canada
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Abstract

The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 5′ region but alternative 3′ ends namely UGT2B7_v5 (containing a novel terminal exon 6b) and _v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (Km). Finally, coimmunoprecipitation experiments support a direct protein–protein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.

Footnotes

    • Received July 25, 2013.
    • Accepted September 30, 2013.
  • This research was supported by the Canadian Institutes of Health Research (CIHR) [Grant MOP-42392]. V.M. received a CIHR Frederick Banting and Charles Best studentship award. G.M. received a studentship award from the Fonds de l’enseignement et de la recherche of the Laval University Faculty of Pharmacy. P.C. received a studentship award from the Fonds de recherches en santé du Québec. C.G. holds the Canada Research Chair in Pharmacogenomics.

  • dx.doi.org/10.1124/dmd.113.053876.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

UGT2B7 Alternative Regulatory Proteins

Vincent Ménard, Pierre Collin, Guillaume Margaillan and Chantal Guillemette
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2197-2205; DOI: https://doi.org/10.1124/dmd.113.053876

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Research ArticleArticle

UGT2B7 Alternative Regulatory Proteins

Vincent Ménard, Pierre Collin, Guillaume Margaillan and Chantal Guillemette
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2197-2205; DOI: https://doi.org/10.1124/dmd.113.053876
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