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

SULT1C 致癌物激活酶的表达、调节和功能

• 批准号: 8630309
• 负责人: Melissa A Runge-Morris
• 金额: $ 41.47万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-08 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630309
• 关键词: 2-Acetylaminofluorene; Address; Adult; Aromatic Amines; Aryl Hydrocarbon Receptor; Bile Acids; Carcinogens; Cell Culture Techniques; Cell Line; Cell model; Cells; Chemicals; Cholesterol; Clinical; Cytosol; DNA Damage; Development; Diabetes Mellitus; Disease; Disease susceptibility; Environment; Environmental Carcinogens; Environmental Exposure; Enzymes; Epithelial Cells; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Heart; Heart Diseases; Hepatic; Hepatocyte; Histocompatibility Testing; Homeostasis; Hormones; Human; Human Development; Human Genome; Individual; Infant; Intestines; Kidney; Kinetics; Knowledge; Large Intestine; Libraries; Life; Light; Lipids; Liver; Malignant Neoplasms; Messenger RNA; Metabolic; Metabolism; Modeling; Molecular; Molecular Models; Nuclear; Nucleic Acid Regulatory Sequences; Organ; Orphan; Pathology; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Plasmids; Play; Positioning Attribute; Predisposition; Process; Property; Proteins; RNA Splicing; Regulation; Relative (related person); Reporter; Research; Rifampin; Role; Safety; Sampling; Signal Pathway; Signal Transduction; Site; Small Intestines; Staging; Sterols; Stimulus; Stomach; Structure; Testing; Tetrachlorodibenzodioxin; Time; Tissues; Toxic effect; Transcript; Transcription Factor 3; Tubular formation; Variant; Vitamin D3 Receptor; Work; Xenobiotics; detoxication; dihydroxy-vitamin D3; drug efficacy; drug metabolism; environmental chemical; enzyme substrate; fetal; induced pluripotent stem cell; inhibitor/antagonist; kidney cell; mRNA Expression; molecular modeling; novel; pharmacophore; postnatal; pregnane X receptor; prenatal; protein expression; public health relevance; receptor; response; rosiglitazone; sulfation; sulfotransferase; transcription factor; treatment effect

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 ? (PPAR?), 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.

描述（由申请人提供）：一个主要的临床挑战是认识到常见疾病，如糖尿病、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，实际上可能起源于人类发育的早期。细胞溶质磺基转移酶（SULT）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在开发阶段SULT 1C表达的差异如何影响药物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SULT 1C表达的表达模式和调节剂，并阐明SULT 1C代谢的底物和抑制剂。与其他异生物质代谢酶不同，SULT 1C主要在胎儿生命期间表达，并且已知将异生物质分子生物活化为有毒和致癌中间体。然而，SULT 1C酶在内源性代谢和生理学中的作用尚未得到表征。我们发现SULT 1C基因受脂质和外源性敏感转录因子的调节，这一发现定义了SULT 1C酶在人类发育和代谢信号传导中心的不可预见的作用，同时也表明SULT 1C酶在生理和外源性环境的界面上起作用。假设：（1）人SULT 1C基因在肝、肾、胃和肠中以及在发育过程中差异表达，（2）这些SULTs的表达受核信号机制的差异调节，这些核信号机制包括法尼醇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（PPR）和过氧化物酶体增殖物激活受体（PPR）。(PPAR?),和异生物质敏感受体异氟烷X受体（PXR）和芳烃受体（AhR），和（3）某些甾醇和/或胆汁酸是SULT 1C酶的内源性底物。为了检验这一假设，本提案的四个具体目标是：（1）确定人SULT 1C 2、SULT 1C 3和SULT 1C 4在来自肝、肾、胃和肠的胎儿、婴儿和成人组织中的表达，（2）确定在肝、肾和肠的细胞模型中控制人SULT 1C 2、SULT 1C 3和SULT 1C 4转录的机制，重点是脂质和外源性物质敏感转录因子的调节，（3）确定在肝分化过程中调节SULT 1C 2转录的机制，（4）确定人SULT 1C酶的结构-功能活性和抑制关系。该项目将为人类SULT 1C基因的表达、调控和功能提供新的线索。获得这种理解是至关重要的，因为SULT 1C酶可能在发育过程中发挥重要的生理作用，并且由于其生物活化有毒和致癌化合物的独特能力，在脆弱的关键窗口期间促进疾病易感性。