Ehmer Ursula, Vogel Arndt, Schütte Jan Karl, Krone Britta, Manns Michael P, Strassburg Christian P
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Hepatology. 2004 Apr;39(4):970-7. doi: 10.1002/hep.20131.
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.
尿苷二磷酸葡萄糖醛酸基转移酶是一类药物代谢酶，参与肝脏药物代谢并抵御环境毒素。本研究旨在鉴定人类UGT1A基因座的多态性，并表征其功能以及与肝细胞癌（HCC）的潜在关联。使用聚合酶链反应和测序分析，对363名受试者（128例HCC患者，235名献血者）血液中的基因组DNA进行UGT1A3、UGT1A4、UGT1A8、UGT1A9、UGT1A10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，分别在25%和15%的样本中检测到A173G变体以及765位的保守G到A交换。UGT1A9在1%和3%的样本中表现出两种变体C3Y和M33T。UGT1A10在2%和13%的样本中表现出保守的核苷酸交换（128 G→A和696 C→T）。在UGT1A3基因中，分别鉴定出W11R、V47A变体以及81位的保守G到A交换，发生率分别为65%、58%和65%。UGT1A4在8%和9%的样本中表现出P24T和L48V变体。UGT1A单核苷酸多态性与HCC无关。UGT1A4的P24T和L48V表现出葡萄糖醛酸化活性降低：β-萘胺分别降低30%和50%，二氢睾酮分别降低50%和0%。总之，人类UGT1A基因座中广泛存在的单核苷酸多态性说明了肝脏代谢个体间差异的遗传基础。肝脏UGT1A4蛋白的两种多态性对诱变胺和内源性类固醇表现出不同的代谢活性，改变了肝脏代谢和解毒功能。
