Expression, Regulation and Function of the SULT1C Carcinogen-Activating Enzymes

描述(申请人提供)：一个主要的临床挑战是认识到糖尿病、动脉粥样硬化性心脏病，甚至一些过去被认为是成人发病的癌症等常见疾病实际上可能起源于人类发育的早期阶段。胞液磺基转移酶(Sults)催化药物、环境化学品、激素、胆固醇和胆汁酸的结合。我们的长期目标是了解SULT1C在发育阶段的表达差异如何影响药物的疗效和安全性，以及对环境致癌物和代谢过程调节剂的敏感性。我们的短期目标是确定SULT1C表达的表达模式和调控因素，并阐明SULT1C代谢的底物和抑制物。与其他外源代谢酶不同，SULT1Cs主要在胎儿时期表达，并被认为可以将外源分子激活为有毒和致癌的中间体。然而，SULT1C酶在内源性代谢和生理中的作用(S)尚不清楚。我们的发现，SULT1C基因受脂质和外源生物感应转录因子的调控，这一发现定义了SULT1C酶在人类发育和代谢信号转导中的不可预见的作用，同时也表明SULT1C酶在生理和外源环境的界面上工作。假设：(1)人类SULT1C基因在肝脏、肾脏、胃和肠道以及发育过程中差异表达，(2)这些SULT1C基因的表达受核信号机制的差异调控，核信号机制包括法尼类X受体(FXR)、肝X受体(LXR)、维生素D受体(VdR)、过氧化物酶体增殖物激活受体γ(PPARγ)以及异种生物敏感受体孕烷X受体(PXR)和芳烃受体(AhR)，以及(3)某些甾醇和/或胆汁酸是SULT1C的内源底物。为了验证这一假设，该建议的四个具体目标是：(1)确定人类SULT1C2、SULT1C3和SULT1C4在胎儿、婴儿和成人肝、肾、胃和肠道组织中的表达；(2)确定在肝、肾和肠道的细胞模型中控制人类SULT1C2、SULT1C3和SULT1C4转录的机制，重点是脂类和外来生物敏感转录因子的调节；(3)确定在肝脏分化过程中调节SULT1C2转录的机制(S)，以及(4)确定人类SULT1C酶的结构与功能活性和抑制关系。该项目将为人类SULT1C基因的表达、调控和功能提供新的线索。了解这一点是至关重要的，因为SULT1C酶可能在发育过程中发挥重要的生理作用，并且由于它们对有毒和致癌化合物具有不同的生物活性，因此在关键的脆弱窗口期间可能会促进疾病的易感性。

DESCRIPTION (provided by applicant): A major clinical challenge is the realization that common diseases such as diabetes, atherosclerotic heart disease, and even some cancers that used to be considered as adult-onset pathologies may actually have their origins during early periods of human development. The cytosolic sulfotransferases (SULTs) catalyze the conjugation of pharmaceuticals, environmental chemicals, hormones, cholesterol, and bile acids. Our long term goal is to understand how differences in SULT1C expression during the stages of development might impact drug efficacy and safety as well as susceptibility to environmental carcinogens and modulators of metabolic processes. Our short-term goals are to determine the expression pattern and regulators of SULT1C expression and to elucidate substrates and inhibitors of SULT1C metabolism. Unlike other xenobiotic- metabolizing enzymes, SULT1Cs are predominantly expressed during fetal life and are known to bioactivate xenobiotic molecules to toxic and carcinogenic intermediates. However, the role(s) of the SULT1C enzymes in endogenous metabolism and physiology are, as yet, uncharacterized. Our discovery that SULT1C genes are regulated by lipid- and xenobiotic-sensing transcription factors defines an unforeseen role for SULT1C enzymes at the heart of human development and metabolic signaling while also indicating that SULT1C enzymes operate at the interface of the physiological and xenobiotic environments. The hypothesis is that (1) the human SULT1C genes are differentially expressed in liver, kidney, stomach, and intestine and during development, (2) expression of these SULTs is differentially regulated by nuclear signaling mechanisms that include the farnesoid X receptor (FXR), the liver X receptor (LXR), the vitamin D receptor (VDR), peroxisome proliferator-activated receptor γ (PPARγ), and the xenobiotic-sensing receptors pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR), and (3) certain sterols and/or bile acids are endogenous substrates for the SULT1C enzymes. To test this hypothesis, the four specific aims of this proposal are to, (1) Determine the expression of human SULT1C2, SULT1C3, and SULT1C4 in fetal, infant, and adult tissue from liver, kidney, stomach, and intestine, (2) Define the mechanisms that control transcription of human SULT1C2, SULT1C3, and SULT1C4 in cellular models of liver, kidney, and intestine, with emphasis on regulation by lipid- and xenobiotic-sensing transcription factors, (3) Define the mechanism(s) that regulate SULT1C2 transcription during hepatic differentiation, and (4) Identify the structure-function activity and inhibition relationships of the human SULT1C enzymes. This project will shed new light on human SULT1C gene expression, regulation, and function. It is essential to obtain this understanding since the SULT1C enzymes likely play important physiological roles during development and, due to their distinct abilities to bioactivat toxic and carcinogenic compounds, are primed to promote disease susceptibility during critical windows of vulnerability.