Krishnaswamy Soundararajan, Hao Qin, Al-Rohaimi Abdul, Hesse Leah M, von Moltke Lisa L, Greenblatt David J, Court Michael H
Molecular Pharmacogenetics Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA 02111, USA.
J Pharmacol Exp Ther. 2005 Jun;313(3):1331-9. doi: 10.1124/jpet.104.081950. Epub 2005 Mar 10.
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.
尿苷二磷酸葡萄糖醛酸基转移酶(UGT)1A6是人类肝脏中的一种主要同工型,它能使众多药物、毒素和内源性底物发生葡萄糖醛酸化,个体间差异很大。尽管这种差异可能涉及遗传和环境因素,但其分子基础仍然未知。利用一个特征明确的人类肝脏库(n = 54)并以血清素葡萄糖醛酸化作为UGT1A6特异性表型标记进行了表型-基因型研究。唯一检测的与表型相关的人口统计学因素是阳性的中度至重度饮酒史(每周超过14杯),且其与血清素葡萄糖醛酸化水平高2倍(p < 0.001)、UGT1A6蛋白含量(p = 0.004)和UGT1A6 mRNA含量(p = 0.025)相关。UGT1A6基因重测序在第1外显子中鉴定出3个非同义多态性(S7A、T181A和R184S)以及5'-调控区(至-2052碱基对)中的8个新多态性。S7A与3个5'-调控区多态性(-1710c→g、-1310del5和-652g→a)完全连锁不平衡。最初的单变量分析未发现任何显著的表型-基因型关联。然而,在没有大量酒精暴露的肝脏中,与非携带者相比,连锁的S7A增强子多态性携带者的UGT1A6 mRNA水平降低了50%(p = 0.026),但对UGT1A6蛋白含量或葡萄糖醛酸化活性没有显著影响。鉴定出三种主要单倍型,包括()1A(参考型)、()1B(-1535g→a和-427g→c)和(*)2(-1710c→g、-1310del5、-652g→a、S7A、T181A和R184S),占等位基因的90%。未发现单倍型与任何表型指标之间存在关联。总之,尽管鉴定出的UGT1A6多态性无法解释观察到的葡萄糖醛酸化差异,但与酒精消费相关的环境因素似乎确实发挥了重要作用。