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，甚至一些癌症，过去被认为是成人发病的病理，实际上可能在人类发育的早期就有其起源。胞质硫转移酶（SULTs）催化药物、环境化学物质、激素、胆固醇和胆汁酸的偶联。我们的长期目标是了解在发展阶段SULT1C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易感性。我们的短期目标是确定SULT1C表达模式和调节因子，并阐明SULT1C代谢的底物和抑制剂。与其他异种代谢酶不同的是，sult1c主要在胎儿时期表达，并且已知可将异种分子生物激活为有毒和致癌中间体。然而，SULT1C酶在内源性代谢和生理中的作用尚未明确。我们发现SULT1C基因受脂质和外源感应转录因子的调节，这一发现定义了SULT1C酶在人类发育和代谢信号传导中的核心作用，同时也表明SULT1C酶在生理和外源环境的界面上起作用。假设是：(1)人类SULT1C基因在肝脏、肾脏、胃和肠以及发育过程中有差异表达；(2)这些SULT1C基因的表达受核信号机制的差异调节，包括法尼脂类X受体（FXR）、肝X受体（LXR）、维生素D受体（VDR）、过氧化物酶体增殖激活受体？（PPAR?）和异种感应受体妊娠烷X受体（PXR）和芳烃受体（AhR），以及(3)某些甾醇和/或胆汁酸是SULT1C酶的内源性底物。为了验证这一假设，本提案的四个具体目标是：(1)确定人SULT1C2、SULT1C3和SULT1C4在胎儿、婴儿和成人肝脏、肾脏、胃和肠道组织中的表达；(2)确定人SULT1C2、SULT1C3和SULT1C4在肝脏、肾脏和肠道细胞模型中的转录控制机制，重点研究脂质和外源传感转录因子的调控。(3)明确肝脏分化过程中调节SULT1C2转录的机制；(4)确定人类SULT1C酶的结构-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思路。由于SULT1C酶可能在发育过程中发挥重要的生理作用，并且由于其对生物激活有毒和致癌化合物的独特能力，在易感性的关键窗口期促进疾病易感性，因此获得这种理解是至关重要的。