Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Drug Metab Pharmacokinet. 2013;28(2):83-92. doi: 10.2133/dmpk.dmpk-12-rv-096. Epub 2012 Oct 23.
Human UDP-glucuronosyltransferase (UGT) 1A1 is the enzyme that detoxifies neurotoxic bilirubin by conjugating it with glucuronic acid. UGT1A1 also plays a critical role in the detoxification and excretion of endogenous and exogenous lipophilic compounds mainly in the liver and gastrointestinal tract. Impaired or reduced UGT1A1 activity causes unconjugated hyperbilirubinemia (Gilbert's syndrome and Crigler-Najjar syndrome) and side effects of drug treatment such as SN-38 (active metabolite of the anticancer drug irinotecan)-induced toxicity. Understanding the regulatory mechanism of human UGT1A1 expression is critical in treating patients with unconjugated hyperbilirubinemia and for effective drug treatment. We identified the distal enhancer module of the UGT1A1 gene and a single nucleotide polymorphism in it that significantly reduces the transcriptional activity associated with the manifestation of Gilbert's syndrome. This review describes the transcriptional regulation of the human UGT1A1 gene by transcription factors and their co-factors, the genetic polymorphism associated with reduced transcriptional activity, and the induction of UGT1A1 expression by non-genetic factors including environmental factors and its pharmacological and toxicological meaning.
人类 UDP-葡糖醛酸基转移酶 (UGT) 1A1 是一种酶，通过与葡糖醛酸结合来解毒神经毒性胆红素。UGT1A1 还在肝脏和胃肠道等主要部位的内源性和外源性亲脂性化合物的解毒和排泄中发挥关键作用。UGT1A1 活性受损或降低会导致未结合高胆红素血症（吉尔伯特综合征和克里格勒-纳贾尔综合征）和药物治疗的副作用，如 SN-38（抗癌药物伊立替康的活性代谢物）引起的毒性。了解人类 UGT1A1 表达的调节机制对于治疗未结合高胆红素血症患者和有效药物治疗至关重要。我们鉴定了 UGT1A1 基因的远端增强子模块及其单核苷酸多态性，该多态性显著降低了与吉尔伯特综合征表现相关的转录活性。本综述描述了转录因子及其共因子对人 UGT1A1 基因的转录调控、与转录活性降低相关的遗传多态性，以及非遗传因素（包括环境因素）诱导 UGT1A1 表达及其药理学和毒理学意义。
