A pharmacogenetics study of the human glucuronosyltransferase UGT1A4.
BACKGROUND
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).


METHODS
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.


RESULTS
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 -5 kb promoter region, five 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 showed limited effect of these variations.


CONCLUSIONS
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 (Val⁴⁸, Asp⁵⁰, Gln⁵⁶, Phe¹⁷⁶, Asn²⁵⁰, Leu²⁷⁶) and are expected to have a potential in vivo effect.
Benoit-Biancamano
Marie-Odile
MO
Pharmacogenomics Laboratory, CHUQ Research Center and Faculty of Pharmacy, Laval University, G1V 4G2 Québec, Canada.
Adam
Jean-Philippe
JP
Bernard
Olivier
O
Court
Michael H
MH
Leblanc
Marie-Hélène
MH
Caron
Patrick
P
Guillemette
Chantal
C
D001741:Black or African American / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
D004364:Pharmaceutical Preparations; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase