Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs:: implication of defects in the UGT1A1 gene promoter
Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs:: implication of defects in the UGT1A1 gene promoter
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DOI：
10.1007/s00210-007-0226-y
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Miwa, Masao
中科院分区：
文献类型：
--
作者：
Sugatani, Junko;Mizushima, Kousuke;Miwa, Masao
人UDP-葡萄糖醛酸基转移酶（UGT）1A 1是一种关键酶，通过与葡萄糖醛酸结合，负责内源性和外源性亲脂性化合物（如潜在神经毒性胆红素和抗癌药物伊立替康SN-38）的解毒和代谢。一个290 bp的远端增强子模块，UGT 1A 1的苯巴比妥响应增强子模块（gtPBREM），完全解释了UGT 1A 1基因的组成型雄甾烷受体（CAR）-、甾烷X受体（PXR）-、糖皮质激素受体（GR）-和芳烃受体（AhR）-介导的激活。本研究表明，与近端启动子基序结合的肝细胞核因子1 α（HNF 1 α）不仅增强了UGT 1A 1的基础报告基因活性，包括远端（-3570/-3180）和近端（-165/-1）区域，还影响了CAR、PXR、GR和AhR对UGT 1A 1的转录调控，从而显著增强了报告基因活性。此外，我们评估了TA重复多态性和gtPBREM T-3279 G突变对CAR、PXR、GR和AhR对UGT 1A 1转录激活的影响。CAR、PXR激活剂利福平、GR激活剂地塞米松和AhR激活剂苯并[a]芘对A（TA）（7）TAA突变体的转录激活作用比T-3279 G变体的转录激活作用降低得更多，同时具有T-3279 G和A（TA）（7）TAA突变的UGT 1A 1启动子的活性仍然较低。因此，UGT 1A 1基因启动子变异，包括TA重复多态性和T-3279 G gtPBREM，具有重要的临床意义。
Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene. This study indicates that hepatocyte nuclear factor 1 alpha (HNF1 alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. Moreover, we assessed the influence of the TA repeat polymorphism and gtPBREM T-3279G mutation on transcriptional activation of UGT1A1 by CAR, PXR, GR, and AhR. Transcriptional activation of the A(TA)(7)TAA mutant by CAR, the PXR activator rifampicin, the GR activator dexamethasone, and the AhR activator benzo[a]pyrene was more reduced than that of the T-3279G variant, and the activity of the UGT1A1 promoter with both T-3279G and A(TA)(7)TAA mutations was still lower. Thus, UGT1A1 gene promoter variations, including the TA repeat polymorphism and T-3279G gtPBREM, have important clinical implications.