Variation of hepatic glucuronidation:: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4
Variation of hepatic glucuronidation:: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4
复制标题
DOI：
10.1002/hep.20131
复制
发表时间：
2004-04-01
期刊：
影响因子：
13.5
通讯作者：
Strassburg, CP
中科院分区：
文献类型：
--
作者：
Ehmer, U;Vogel, A;Strassburg, CP
UDP-葡萄糖醛酸转移酶是一个药物代谢酶家族，有助于肝脏药物代谢和保护免受环境毒素的影响。本研究的目的是确定人类UGT1A基因位点的多态性，并描述其功能和与肝细胞癌（HCC）的潜在关联。采用聚合酶链反应和测序技术对363例受试者（128例HCC患者，235例献血员）的基因组DNA进行UGT 1A3、UGT 1A4、UGT 1A8、UGT 1A9、UGT 1A10基因多态性分析。通过活性测定分析重组变体UGT蛋白。在UGT1A8基因中，A173G变体和765位保守的G至A交换分别在25%和15%中检测到。UGT1A9在1%和3%中表现出两种变体C3Y和M33T。UGT1A10在2%和13%中表现出保守的核苷酸交换（128 G--> A和696 C--> T）。在UGT1A3基因中，W11R、V47A变体和81位保守的G至A交换的发生率分别为65%、58%和65%。UGT1A4在8%和9%中表现出P24T和L48V变体。UGT1A SNPs与HCC无关。UGT 1A4 P24 T和L48 V显示葡萄糖醛酸化活性降低：β-萘胺分别为30%和50%，二氢睾酮分别为50%和0%。总之，在整个人类UGT1A基因位点SNP的高患病率说明了肝脏代谢个体间变异的遗传基础。肝脏UGT1A4蛋白的两种多态性表现出对致突变胺和内源性类固醇的不同代谢活性，改变肝脏代谢和解毒。
UDP-glucuronosyltransferases are a family of drug metabolizing enzymes contributing to hepatic drug metabolism and protection against environmental toxins. The aim of this study was to identify polymorphisms at the human UGT1A gene locus and to characterize their function and potential association with hepatocellular carcinoma (HCC). Genomic DNA from the blood of 363 subjects (128 patients with HCC, 235 blood donors) was analyzed for polymorphisms of the UGT1A3, UGT1A4, UGT1A8, UGT1A9, UGT1A10 genes using polymerase chain reaction, sequencing analysis. Recombinant variant UGT protein was analyzed by activity assays. In the UGT1A8 gene an A173G variant and a conserved G to A exchange at position 765 were detected in 25% and 15%. UGT1A9 exhibited two variants C3Y and M33T in 1% and 3%. UGT1A10 exhibited conserved nucleotide exchanges (128 G-->A and 696 C-->T) in 2% and 13%. In the UGT1A3 gene a W11R, a V47A variant, and a conserved G to A exchange at position 81 with an incidence of 65%, 58%, and 65%, respectively, were identified. UGT1A4 exhibited a P24T and an L48V variant in 8% and 9%. UGT1A SNPs were not associated with HCC. UGT1A4 P24T and L48V exhibited reduced glucuronidation activities: beta-naphthylamine 30% and 50%, and dihydrotestosterone 50% and 0%, respectively. In conclusion, the high prevalence of SNPs throughout the human UGT1A gene locus illustrates a genetic basis of interindividual variations of hepatic metabolism. Two polymorphisms of the hepatic UGT1A4 protein show a differential metabolic activity toward mutagenic amines and endogenous steroids, altering hepatic metabolism and detoxification.