Personne :
Guillemette, Chantal

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Université Laval. Faculté de pharmacie
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Voici les éléments 1 - 4 sur 4
  • Publication
    Accès libre
    UGT genomic diversity : beyond gene duplication
    (Informa Healthcare, 2009-10-26) Lévesque, Éric; Bellemare, Judith.; Harvey, Mario.; Ménard, Vincent; Guillemette, Chantal
    The human uridine diphospho (UDP)-glucuronosyltransferase (UGT) superfamily comprises enzymes responsible for a major biotransformation phase II pathway: the glucuronidation process. The UGT enzymes are located in the endoplasmic reticulum of almost all tissues, where they catalyze the inactivation of several endogenous and exogenous molecules, including bilirubin, sex steroids, numerous prescribed drugs, and environmental toxins. This metabolic pathway is particularly variable. The influence of inheritable polymorphisms in human UGT-encoding genes has been extensively documented and was shown to be responsible for a fraction of the observed phenotypic variability. Other key genomic processes are likely underlying this diversity; these include copy-number variations, epigenetic factors, and newly discovered splicing mechanisms. This review will discuss novel molecular aspects that may be determinant to UGT phenotypes.
  • Publication
    Accès libre
    A rare UGT2B7 variant creates a novel N-glycosylation site at codon 121 with impaired enzyme activity
    (American Society for Pharmacology and Experimental Therapeutics, 2016-09-12) Benoît-Biancamano, Marie-Odile; Desjardins, Sylvie; Guillemette, Chantal; Girard-Bock, Camille; Villeneuve, Lyne
    UDP-glucuronosyltransferase (UGT) superfamily are glycoproteins resident of the endoplasmic reticulum membranes that undergo post-translational modifications (PTM). UGT2B7 is of particular interest because of its action on a wide variety of drugs. Most studies currently survey common variants and are only examining a small fraction of the genetic diversity. However, rare variants (frequency <1%) might have significant effect as they are predicted to greatly outnumber common variants in the human genome. Here, we discovered a rare single nucleotide UGT2B7 variant of potential pharmacogenetic relevance that encodes a nonconservative amino acid substitution at codon 121. This low-frequency variation, found in two individuals of a population of 305 healthy volunteers, leads to the translation of an asparagine (Asn) instead of an aspartic acid (Asp) (UGT2B7 p.D121N). This amino acid change was predicted to create a putative N-glycosylation motif NX(S/T) subsequently validated upon endoglycosidase H treatment of microsomal fractions and inhibition of N-glycosylation of endogenously produced UGT2B7 with tunicamycin from HEK293 cells. The presence of an additional N-linked glycan on the UGT2B7 enzyme, likely affecting proper protein folding, resulted in a significant decrease, respectively by 49 and 40%, in the formation of zidovudine and mycophenolic acid glucuronides. A systematic survey of the dbSNP database uncovered 32 rare and naturally occurring missense variations predicted to create or disrupt N-glycosylation sequence motifs in the other UGT2B enzymes. Collectively, these variants have the potential to increase the proportion of variance explained in the UGT pathway due to changes in PTM such as N-linked glycosylation with consequences on drug metabolism.
  • Publication
    Accès libre
    Pharmacogenomics of human uridine diphospho-glucuronosyltransferases (UGTs) and clinical implications
    (Wiley, 2014-06-12) Lévesque, Éric; Rouleau, Michèle; Guillemette, Chantal
    Glucuronidation, mediated by UDP-glucuronosyltransferase enzymes (UGTs), is a major phase II biotransformation pathway and, complementary to phase I metabolism and membrane transport, one of the most important cellular defense mechanism responsible for the inactivation of therapeutic drugs, other xenobiotics and numerous endogenous molecules. Individual variability in UGT enzymatic pathways is significant and may have profound pharmacological and toxicological implications. Several genetic and genomic processes are underlying this variability and are discussed in the context of drug metabolism and diseases such as cancer.
  • Publication
    Accès libre
    A pharmacogenetics study of the human glucuronosyltransferase UGT1A4
    (Lippincott Williams & Wilkins, 2009-12-01) Benoît-Biancamano, Marie-Odile; Leblanc, Marie-Hélène; Bernard, Olivier; Court, Michael H.; Guillemette, Chantal; Caron, Patrick; Adam, Jean-Philippe
    UGT1A4 is primarily expressed in the liver and exhibits catalytic activities for various drugs. Amongst the few UGT1A4 polymorphisms evaluated, studies support the alteration of UGT1A4-mediated glucuronidation by a few variations including the Pro24Thr and Leu48Val variants (referred to as UGT1A4*2 and *3). We therefore investigated genetic mechanisms that might contribute to interindividual variation in UGT1A4 expression and activity. The UGT1A4 gene was sequenced from -4963 bp relative to the ATG to 2000 bp after the first exon in 184 unrelated Caucasians and African-Americans. We identified a large number of genetic variations, including 13 intronic, 39 promoter, as well as 14 exonic polymorphisms, with 10 that lead to aminoacid changes. Of the nucleotide variations found in the -5kb promoter region, 5 are located in the proximal region (first 500 bp), and positioned in putative HNF-1 and OCT-1 binding sites. Four of these variants, placed at -163, -219, -419 and -463, are in complete linkage disequilibrium with the Leu48Val coding region variant and with several variants in the upstream region of the promoter. Transient transfections of reference and variant promoter constructs (from position -500 to +1) in different cell lines with or without co-expression of HNF-1 and/or OCT-1, demonstrated limited effect of these variations. However, several coding variants significantly modified the enzyme kinetics for tamoxifen and Z-4-hydroxytamoxifen (Val48, Asp50, Gln56, Phe176, Asn250, Leu276). Our results reveal that, despite a large number of polymorphisms located in the promoter region, the exonic variants are those expected to have a potential in vivo effect.