Document Detail


A pharmacogenomics study of the human estrogen glucuronosyltransferase UGT1A3.
MedLine Citation:
PMID:  17558304     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
UGT1A3 is one of the most efficient at conjugating estrone, a precursor for biosynthesis of estradiol in peripheral tissues. We established the genetic mechanisms that might contribute to individual variation in UGT1A3 expression and activity. UGT1A3 first exon and 5'-flanking regions were sequenced in 249 Caucasians. We identified 17 polymorphisms, among them seven regulatory and 10 exonic polymorphisms with six leading to amino-acid changes. Luciferase reporter assays, site-directed mutagenesis and electrophoretic mobility shift assays using hepatoma HepG2 cells were carried out to show functionality of variant promoters. Reduced transcriptional activity was associated with all six variant promoters (two-fold; P<0.001). One of the potential mechanisms would involve the -148 T>C and -581 C>T variations that modulate gene function by affecting hepatocyte nuclear factor-1alpha and hepatocyte nuclear factor-4alpha binding, respectively. Then, estrone-conjugating activity was assessed with 11 heterologously expressed allozymes. Three phenotypes were observed; UGT1A3*1, *2 (WR, VA) and *3 (WR) with high intrinsic clearance values; UGT1A3*5 (QR, WR), *7 (FI), *9 (WR, ML), *10 (VA) and *11 (WR, VA and MI) had intermediate CLint (2X-10X lower vs. *1), whereas UGT1A3*4 (RW), *6 (WR, VA, MV) and *8 (AV) had low CLint (>10X lower vs. *1). Diplotype analyses indicate that 20.1% of individuals carry two alleles affecting UGT1A3 expression and/or activity. This study did not investigate genotype-phenotype association, but raise the possibility that genetically determined variation might contribute to variability in the inactivation of estrone by UGT1A3 and subsequent changes in lifetime exposure to estrogens potentially modifying risk of cancer.
Authors:
Bertrand Caillier; Johanie Lépine; Jelena Tojcic; Vincent Ménard; Louis Perusse; Alain Bélanger; Olivier Barbier; Chantal Guillemette
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  17     ISSN:  1744-6872     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-11     Completed Date:  2007-08-20     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  481-95     Citation Subset:  IM    
Affiliation:
Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUQ Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AY724450;  AY724451;  AY724452;  AY724453;  AY724454;  AY724455;  DQ408604
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MeSH Terms
Descriptor/Qualifier:
5' Flanking Region
Base Sequence
Cell Line
DNA / genetics,  metabolism
Estrone / metabolism
European Continental Ancestry Group / genetics
Exons
Female
Genetic Variation
Glucuronosyltransferase / genetics*,  metabolism*
Haplotypes
Humans
Kinetics
Molecular Sequence Data
Mutagenesis, Site-Directed
Pharmacogenetics
Phenotype
Polymorphism, Genetic
Promoter Regions, Genetic
Protein Binding
Recombinant Proteins / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Recombinant Proteins; 53-16-7/Estrone; 9007-49-2/DNA; EC 2.4.1.-/UDP-glucuronosyltransferase, UGT1A3; EC 2.4.1.17/Glucuronosyltransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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