UGT genomic diversity: beyond gene duplication

Guillemette, Chantal; Lévesque, Éric; Harvey, Mario; Bellemare, Judith; Ménard, Vincent

doi:10.3109/03602530903210682

Cited by 121 publications

(47 citation statements)

References 123 publications

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“…However, underlying factors (LATFs, liver-enriched transcription factors as well as genetic diversity [64]) are difficult to distinguish. In addition, recent evidence supports the concept that UGT proteins interact as dimers/oligomers which may have implications for structure, function and substrate specificity of UGTs [65].…”

Section: Species Differences Of Rat and Human Hepatic Ugt Induction Bmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Section: Species Differences Of Rat and Human Hepatic Ugt Induction Bmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

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“…2) [25]. UGT enzymes are widely and differentially expressed throughout the human body [26]. Although the majority of UGT enzymes are expressed in the liver, UGT1A7, 1A8, and 1A10 are expressed exclusively extrahepatically, mainly in the intestine [27,28]; UGT1A9, 2B7, and 2B11 are expressed at relatively high amounts in the kidney.…”

Section: Glucuronidation Enzymesmentioning

confidence: 99%

Effects of Herbal Supplements on Drug Glucuronidation. Review of Clinical, Animal, andIn VitroStudies

Mohamed

Frye

2010

Planta Med

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“…This post-transcriptional mechanism has been reported for genes involved in drug metabolism, most notably cytochrome P450 (P450) (Turman et al, 2006), sulfotransferases (He et al, 2005), glutathione S-transferase (Ross and Board, 1993), and UDP-glucuronosyltransferases (UGTs) . UGT1A family members are derived from the use of alternative promoters and exons 1, whereas UGT2B7 is subjected to extensive alternative splicing (Innocenti et al, 2008;Guillemette et al, 2010;Ménard et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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 59 region but alternative 39 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 (K m ). Finally, coimmunoprecipitation experiments support a direct proteinprotein 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.

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UGT genomic diversity: beyond gene duplication

Cited by 121 publications

References 123 publications

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Effects of Herbal Supplements on Drug Glucuronidation. Review of Clinical, Animal, andIn VitroStudies

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

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