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

摘要

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 resequenc-ing identified three nonsynonymous polymorphisms (S7A,T181 A,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 pheno-type-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.