A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity
A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity
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DOI：
10.1016/j.clpt.2003.10.006
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发表时间：
2004-03-01
影响因子：
6.7
通讯作者：
Guillemette, C
中科院分区：
文献类型：
--
作者：
Duguay, Y;Báár, C;Guillemette, C
为了阐明吗啡代谢变异性的分子决定因素，我们研究了尿苷二磷酸-葡萄糖醛基转移酶2B7 （UGT2B7）基因的遗传多态性，并在体外和接受长期吗啡治疗的癌症患者中评估了它们的功能影响。遗传分析显示存在8个单核苷酸多态性（SNPs），其中6个紧密相连，位于相对于肝起始位点的-1248，-1241,-1054,-842，-268和-102位置。相反，-66位的SNP独立发生，而-79位的新变异似乎与密码子268 SNP （UGT2B7*2）处于连锁不平衡状态。在最初的SNP筛选中，在白人受试者中观察到至少4个单倍型。在体外功能鉴定中，-79变异启动子报告基因构建体在Caco-2结肠细胞和HepG2肝癌细胞中的活性分别比野生型构建体低2.5- 7倍（P = 0.015和P < 0.001）。为了研究体内-79变异的可能影响，采用液相色谱-质谱法测定了长期口服吗啡治疗的癌症患者血清吗啡和吗啡葡糖苷浓度，并对受试者进行了-79多态性基因分型。175例肝肾功能正常的患者中，6例为杂合子，变异率为-79，与169例非携带者相比，吗啡-6-葡糖苷(M6G)/吗啡和吗啡-3-葡糖苷(M3G)/吗啡比值分别为5.9 +/- 3.5和7.1 +/- 7.0 (P = 0.96)，吗啡-3-葡糖苷(M3G)/吗啡比值分别为31.2 +/- 17.1和42.9 +/- 31.2 （P = 0.53）。UGT2B7基因-79多态性可能的临床相关性需要在更大的样本中进行进一步的研究。
To clarify the molecular determinants of the metabolic variability of morphine, we searched for genetic polymorphisms in the gene for uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) and evaluated their functional impact in vitro and in patients with cancer receiving long-term morphine therapy. Genetic analysis revealed the existence of 8 single-nucleotide polymorphisms (SNPs), 6 of which are tightly linked and are at positions -1248, -1241, -1054, -842, -268, and -102 relative to the hepatic start site. In contrast, an SNP at position -66 occurs independently, whereas a novel variation at position -79 appears to be in linkage disequilibrium with the codon 268 SNP (UGT2B7*2). At least 4 haplotypes were observed in white subjects included in the initial SNP screening. On functional in vitro characterization, promoter-reporter gene constructs with the -79 variation displayed 2.5- to 7-fold less activity compared with the wild-type construct in Caco-2 colon cells and HepG2 hepatoma cells, respectively (P = .015 and P < .001, respectively). To investigate a possible effect of the -79 variation in vivo, serum morphine and morphine glucuronide concentrations were measured by liquid chromatography mass spectrometry in patients with cancer who received long-term oral morphine therapy, and subjects were then genotyped for the -79 polymorphism. Among 175 patients with normal hepatic and renal function, 6 were heterozygous for the -79 variation, and the morphine-6-glucuronide (M6G)/morphine and morphine-3-glucuronide (M3G)/morphine ratios versus those in the 169 noncarriers were 5.9 +/- 3.5 versus 7.1 +/- 7.0 for M6G/morphine (P = .96) and 31.2 +/- 17.1 versus 42.9 +/- 31.2 for M3G/morphinc (P = .53), respectively. Further studies in larger samples are needed to make conclusions about the possible clinical relevance of the -79 polymorphism in the UGT2B7 gene.