Received for publication February 28, 2007.
Revised August 19, 2007.
Accepted for publication August 29, 2007.

Lack of association between common polymorphisms in UGT1A9 and gene expression and activity

Abstract

Interindividual variability in the glucuronidation of xenobiotics metabolized by UDP-glucuronosyltransferase 1A9 (UGT1A9) suggests the presence of functional UGT1A9 variants. The aim of this study was to evaluate whether the putative functionality of the UGT1A9 variants -118T_9>10 (rs3832043), I399C>T (rs2741049), -275T>A (rs6714486)and -2152C>T (rs17868320) could be confirmed in an independent study. UGT1A9 genotypes and UGT1A9 activity (i.e., flavopiridol and mycophenolic acid glucuronidation) were determined in 46 Caucasian human livers. mRNA levels were quantitated by real-time polymerase chain reaction in 35 of these livers. In addition, samples from 60 unrelated Caucasians belonging to the HapMap Project were also genotyped, in order to confirm the allele frequencies and linkage disequilibrium (LD) pattern observed in our Caucasian livers. The allele frequencies of the -118T_9>10, I399C>T, -275T>A and -2152C>T variants were 0.39, 0.39, 0.02 and 0.02 in the livers, respectively. The I399C>Tvariant was in complete LD (r²=1) with -118T_9>10 (linked alleles: C and T9, respectively). Complete LD between these two variants was also found in the HapMap samples (frequencies of -118T_9>10 and I399C>T=0.38). I399C>T and -118T_9>10 correlated with neither UGT1A9 activities nor mRNA levels. Due to the low frequencies of the -275T>A and -2152C>T variants, an effect on phenotype could not be evaluated. Our data demonstrate that the common I399C>T and -118T_9>10 polymorphisms do not explain interindividual variation in hepatic UGT1A9 activity and mRNA expression, and are in complete LD, in the donor liver samples we studied.

Key words: genetic polymorphism, glucuronidation, liver microsomes, UDP glucuronyltransferases

This article has been cited by other articles:

				E. Cecchin, F. Innocenti, M. D'Andrea, G. Corona, E. De Mattia, P. Biason, A. Buonadonna, and G. Toffoli Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan J. Clin. Oncol., May 20, 2009; 27(15): 2457 - 2465. [Abstract] [Full Text] [PDF]

				Y. Saito, K. Sai, K. Maekawa, N. Kaniwa, K. Shirao, T. Hamaguchi, N. Yamamoto, H. Kunitoh, Y. Ohe, Y. Yamada, et al. Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese Drug Metab. Dispos., February 1, 2009; 37(2): 272 - 276. [Abstract] [Full Text] [PDF]