Journal article
A pharmacogenetics study of the human glucuronosyltransferase UGT1A4
Pharmacogenetics and genomics, Vol.19(12), pp.945-954
12/2009
Handle:
https://hdl.handle.net/2376/111894
PMCID: PMC6177227
PMID: 19890225
Abstract
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 Pro
24
Thr and Leu
48
Val 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 amino-acid 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 Leu
48
Val 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. Additional functional studies on promoter variants are still required to predict their potential influence on
UGT1A4
expression
in vivo
. Besides, several coding variants significantly modified the enzyme kinetics for tamoxifen and Z-4-hydroxytamoxifen (Val
48
, Asp
50
, Gln
56
, Phe
176
, Asn
250
, Leu
276
) and are expected to have a potential
in vivo
effect.
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Details
- Title
- A pharmacogenetics study of the human glucuronosyltransferase UGT1A4
- Creators
- Marie-Odile Benoit-Biancamano - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, CanadaJean-Philippe Adam - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, CanadaOlivier Bernard - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, CanadaMichael H Court - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MassachusettsMarie-Hélène Leblanc - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, CanadaPatrick Caron - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, CanadaChantal Guillemette - Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2, Québec, Canada
- Publication Details
- Pharmacogenetics and genomics, Vol.19(12), pp.945-954
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Identifiers
- 99900547549701842
- Language
- English
- Resource Type
- Journal article