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

Pharmacogenetics. 2004 Aug;14(8):501-15. doi: 10.1097/01.fpc.0000114754.08559.27.

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • African Americans
  • Aged
  • Base Sequence
  • Child
  • Child, Preschool
  • European Continental Ancestry Group
  • Female
  • Genotype
  • Glucuronates / metabolism
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Haplotypes / genetics
  • Humans
  • Male
  • Microsomes, Liver / enzymology*
  • Middle Aged
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic / genetics*

Substances

  • Glucuronates
  • Glucuronosyltransferase
  • UDP-glucuronosyltransferase 1A9

Associated data

  • GENBANK/AF481810
  • GENBANK/AY273792
  • GENBANK/AY282534
  • GENBANK/AY282535
  • GENBANK/AY282537
  • GENBANK/AY282538
  • GENBANK/AY282539
  • GENBANK/AY282541
  • GENBANK/AY282542
  • GENBANK/AY326394
  • GENBANK/AY345903