Received for publication December 8, 2004.
Revised March 3, 2005.
Accepted for publication March 3, 2005.

UDP-glucuronosyltransferase (UGT) 1A6 pharmacogenetics: 1. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation

Abstract

UDP-glucuronosyltransferase (UGT) 1A6 is a major isoform in human liver that glucuronidates numerous drugs, toxins and endogenous substrates with high interindividual variability. The molecular basis for this variability remains unknown, although it likely involves genetic and environmental factors. Phenotype-genotype studies were conducted using a well-characterized human liver bank (n=54) and serotonin glucuronidation as a UGT1A6-specific phenotype marker. A positive moderate to heavy alcohol use history (> 14 drinks per week) was the only demographic factor examined that correlated with phenotype, and was associated with 2-fold higher serotonin glucuronidation (p<0.001), UGT1A6 protein content (p=0.004) and UGT1A6 mRNA content (p=0.025). UGT1A6 gene resequencing identified three nonsynonymous polymorphisms (S7A, T181A, and R184S) in exon 1 and 8 novel polymorphisms in the 5'-regulatory region (to -2,052 bp). S7A was in complete linkage disequilibrium with three 5'-regulatory region polymorphisms (-1710c>g, -1310del5, and -652g>a). Initial univariate analyses did not identify any significant phenotype-genotype associations. However, in livers without substantial alcohol exposure, 50% lower UGT1A6 mRNA levels (p=0.026) were found in carriers of the linked S7A-enhancer polymorphisms compared with non-carriers but without significant effect on UGT1A6 protein content or glucuronidation activities. Three major haplotypes, including *1A (reference), *1B (-1535g>a, -427g>c), and *2 (-1710c>g, -1310del5, -652g>a, S7A, T181A, R184S), were identified, accounting for 90% of alleles. No association of haplotype with any of the phenotype measures could be discerned. In conclusion, although the identified UGT1A6 polymorphisms did not explain the observed glucuronidation variability, there does appear to be a significant role for environmental factors associated with alcohol consumption.

Key words: Glucuronidation, Pharmacogenetics, UDP-glucuronosyltransferase, drug metabolism, in vitro, liver

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