OV-A-3.

Background/aims: UDP-glucuronosyltransferase UGT1A3 is significant for the glucuronic acid conjugation of a diversity of endo- and xenobiotics in the liver. Considering the variability in UGT1A3-mediated hepatic glucuronidation activity, this study was designed to identify common UGT1A3 genetic variants and determine their potential for contributing to interindividual differences.Methods: Single nucleotide polymorphism (SNP) discovery was accomplished by resequencing DNA samples from healthy Caucasians. Haplotypes were inferred and population frequencies estimated using PHASE version 2.1. For functional analysis, we used HepG2 cells in transfection studies with UGT1A3/luciferase constructs and electromobility shift assays.Results: Sequence analysis revealed six UGT1A3 upstream SNPs and 4 common (3-26%) promoter region haplotypes were inferred. One of the promoter variants fell within a putative binding factor site for the hepatocyte nuclear factor (HNF)-1α at -148 and is associated with a significant decrease in luciferase activity. The −148 T>C variant significantly decreased by 50% the binding of the protein complex while the HNF1α-specific antibody was able to supershift entirely the DNA-protein complex.Conclusion: UGT1A3 common promoter haplotype variants modulate gene function, namely through a reduction of the HNF1α-mediated promoter activation, and might contribute to interindividual differences in UGT1A3-mediated glucuronidation.Clinical Pharmacology & Therapeutics (2005) 79, P35–P35; doi: 10.1016/j.clpt.2005.12.124 [ABSTRACT FROM AUTHOR]