Journal article
UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: I. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation
The Journal of pharmacology and experimental therapeutics, Vol.313(3), pp.1331-1339
06/2005
Handle:
https://hdl.handle.net/2376/111821
PMID: 15761114
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 eight novel polymorphisms in the 5'-regulatory region (to -2052 base pairs). 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 noncarriers but without significant effect on UGT1A6 protein content or glucuronidation activities. Three major haplotypes, including (*)1A (reference), (*)1B (-1535g-->a and -427g-->c), and (*)2 (-1710c-->g, -1310del5, -652g-->a, S7A, T181A, and 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 seem to be a significant role for environmental factors associated with alcohol consumption.
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Details
- Title
- UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: I. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation
- Creators
- Soundararajan Krishnaswamy - Molecular Pharmacogenetics Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA 02111, USAQin HaoAbdul Al-RohaimiLeah M HesseLisa L von MoltkeDavid J GreenblattMichael H Court
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.313(3), pp.1331-1339
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- DK-58496 / NIDDK NIH HHS GM-61834 / NIGMS NIH HHS DA-05258 / NIDA NIH HHS AG-17880 / NIA NIH HHS RR-00054 / NCRR NIH HHS AT-01381 / NCCIH NIH HHS DA-13209 / NIDA NIH HHS MH-58435 / NIMH NIH HHS AI-058784 / NIAID NIH HHS
- Identifiers
- 99900547412001842
- Language
- English
- Resource Type
- Journal article