Sugatani Junko, Mizushima Kousuke, Osabe Makoto, Yamakawa Kasumi, Kakizaki Satoru, Takagi Hitoshi, Mori Masatomo, Ikari Akira, Miwa Masao
Department of Pharmaco-Biochemistry, Global Center of Excellence for Innovation in Human Health Sciences, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):597-605. doi: 10.1007/s00210-007-0226-y. Epub 2008 Jan 3.
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 1alpha (HNF1alpha) 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.
人尿苷二磷酸葡萄糖醛酸基转移酶（UGT）1A1是一种关键酶，负责通过与葡萄糖醛酸结合对内源性和外源性亲脂性化合物进行解毒和代谢，如具有潜在神经毒性的胆红素和抗癌药物伊立替康SN - 38。一个290bp的远端增强子模块，即UGT1A1的苯巴比妥反应性增强子模块（gtPBREM），完全介导组成型雄甾烷受体（CAR）、孕烷X受体（PXR）、糖皮质激素受体（GR）和芳烃受体（AhR）对UGT1A1基因的激活。本研究表明，与近端启动子基序结合的肝细胞核因子1α（HNF1α）不仅增强了UGT1A1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CAR、PXR、GR和AhR对UGT1A1的转录调控，从而显著增强报告基因活性。此外，我们评估了TA重复多态性和gtPBREM T - 3279G突变对CAR、PXR、GR和AhR介导的UGT1A1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对T - 3279G变体的抑制作用更强，同时具有T - 3279G和A(TA)(7)TAA突变的UGT1A1启动子活性仍然较低。因此，UGT1A1基因启动子变异，包括TA重复多态性和T - 3279G gtPBREM，具有重要的临床意义。
