Identification of common polymorphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver.

Abstract

Polymorphisms in UDP-glucuronosyltransferases (UGTs) can influence detoxifying capacities and have considerable therapeutic implications in addition to influence various (patho)physiological processes. UGT1A9 plays a central role in the metabolism of various classes of therapeutic drugs in addition to carcinogens and steroids. The great interindividual variability of UGT1A9-mediated glucuronidation remains poorly explained, while evidence for its genetic origin exists. The proximal UGT1A9 promoter was screened for polymorphisms by sequencing and, the contribution of single nucleotide polymorphisms (SNPs) to the variability of UGT1A9 protein levels and activity was evaluated. We confirmed the presence of the -109 to -98 T10 polymorphism and found ten novel SNPs that generated a diversity of haplotypes in two independent populations. In a panel of 48 human liver microsomes, the UGT1A9 expression varied by 17-fold and was significantly correlated with SNPs -275, -331/-440, -665 and -2152. The base insertion T10 reported to increase reporter gene expression in HepG2 cells [] was not linked to -275 and -2152 SNPs and was not associated with changes in UGT1A9 protein levels. Compared to wild-type individuals, there were statistically significant higher glucuronidating activities in livers with the -275 and -2152 using mycophenolic acid and propofol as UGT1A9 substrates, indicating an extensive glucuronidator phenotype associated with these variants. This is the first study to demonstrate that naturally occurring sequence variations in the UGT1A9 promoter are informative in predicting the levels of protein and glucuronidating activity, providing a potential mechanism for interindividual variation in UGT1A9-mediated metabolism.