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: 10570232
• 负责人: Melissa A Runge-Morris
• 金额: $ 62.4万
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570232
• 关键词: Address; Adult; Affect; Binding; Biological Assay; Birth; Carcinogens; Cells; Chemicals; Chromatin; Cytoplasm; Data; Development; Developmental Process; Disease; Environment; Environmental Exposure; Environmental Pollutants; Enzymatic Biochemistry; Enzymes; Estrogens; Estrone sulfotransferase; Fetal Liver; Fetus; Food; Genes; Genetic Transcription; Hepatic; Hepatocyte; High-Throughput Nucleotide Sequencing; Hormones; Human; Human Activities; Human Development; In Situ; Individual; Investigation; Kinetics; Knowledge; Life; Life Cycle Stages; Liver; Metabolic; Metabolism; Modeling; Molecular; Neurotransmitters; Nucleic Acid Regulatory Sequences; Pattern; Pharmaceutical Preparations; Physiological; Placenta; Predisposition; Pregnancy; Probability; Prodrugs; Property; Qualifying; Regulation; Reporter; Research; Role; Specimen; Sterols; Structure; Substrate Specificity; Testing; Time; Toxic effect; Transposase; Xenobiotics; carcinogenicity; chromatin immunoprecipitation; cofactor; fetal; genome-wide; human model; induced pluripotent stem cell; insight; knock-down; liver development; molecular modeling; monoamine-sulfating phenol sulfotransferase; pharmacophore; prenatal; programs; small hairpin RNA; stem cell model; sulfotransferase; transcription factor; vector

The cytosolic sulfotransferase (SULT) conjugating enzymes have the dual ability to metabolize endogenous compounds and xenobiotics, with consequences that include enhanced drug elimination, prodrug activation, hormone inactivation, and pro-carcinogen bioactivation. Unlike most other classes of xenobiotic-metabolizing enzymes, several SULTs are prominently expressed during prenatal life, implying that these enzymes perform important physiological functions in the developing human. Also, although the maternal liver and placenta protect the fetus against xenobiotic exposures, many xenobiotics can cross the placental barrier, making the SULTs especially important determinants of the impact of xenobiotic exposures on developmental processes. Our research group has shed new light on the hepatic expression patterns of the SULTs during human development. For example, we were the first to show that human estrogen sulfotransferase (SULT1E1), a major estrogen-inactivating enzyme, is robustly expressed in liver during gestation and substantially down- regulated after birth. However, the mechanisms that control the temporal expression of SULT1E1 and other prenatally-expressed SULTs, such as SULT1C2, are unknown. Also, the substrate specificities and enzymatic mechanisms of some SULTs are not adequately defined. In the proposed project, we will determine the mechanisms that control SULT1C2 and 1E1 expression during human liver development and will characterize in detail the enzymology of SULT1C2, one of the least studied of the SULTs, in order to understand its function in the developing human. We hypothesize that expression of the SULT1C2 and 1E1 genes is first upregulated and subsequently downregulated during human hepatocyte differentiation through the concerted action of a network of liver-enriched transcription factors, additional differentiation-associated transcription factors, and coregulators. We further hypothesize that the major substrates of SULT1C2 include endogenous molecules that are abundant during prenatal life as well as multiple classes of xenobiotics, and that substrate selectivity and catalytic activity are markedly influenced by structural rearrangements that are induced by binding of the SULT co-factor 3'-phosphoadenosine-5'-phosphosulfate. The specific aims of this project are to: (1) define the region(s) of the SULT1C2 and 1E1 genes that control their transcription in models of human hepatocyte differentiation; (2) identify the transcription factors and coregulators that control SULT1C2 and 1E1 transcription in models of human hepatocyte differentiation and in human liver specimens; and (3) characterize the structure-function activity of human SULT1C2. This project will increase our fundamental knowledge about the mechanisms that control endogenous and foreign chemical metabolism during human development, uncover new information about the function of a major SULT that is expressed during prenatal life, and provide new insight into the types of environmental exposures that could dysregulate SULT expression and function during this most vulnerable period of life.

细胞溶质磺基转移酶（SULT）结合酶具有代谢内源性 化合物和外源性物质，其结果包括增强的药物消除，前药活化， 激素失活和促癌物质生物活化。与大多数其他种类的异生物质代谢不同， 酶，一些SULT显着表达在产前生活，这意味着这些酶执行， 重要的生理功能。另外，虽然母亲的肝脏和胎盘 为了保护胎儿免受外源性物质的暴露，许多外源性物质可以穿过胎盘屏障， SULT是外源性暴露对发育过程影响的特别重要的决定因素。 我们的研究小组已经揭示了在人类发育过程中SULT的肝脏表达模式的新的光。 发展例如，我们是第一个证明人类雌激素磺基转移酶（SULT 1 E1），一种 主要的雌激素失活酶，在妊娠期间在肝脏中强烈表达，并大幅下降 在出生后进行调节。然而，控制SULT 1 E1和其他基因的时间表达的机制， 产前表达的SULT，如SULT 1C 2，是未知的。此外，底物特异性和酶 一些SULT的机制没有充分定义。在拟议项目中，我们将确定 控制人类肝脏发育过程中SULT 1C 2和1 E1表达的机制，并将表征 详细介绍SULT 1C 2的酶学，这是研究最少的SULT之一，以了解其功能 在发展中的人类。我们假设SULT 1C 2和1 E1基因的表达首先上调， 并随后在人肝细胞分化过程中通过以下因素的协同作用下调： 肝脏富集的转录因子网络，另外的分化相关转录因子，和 协同调节因子我们进一步假设SULT 1C 2的主要底物包括内源性分子 以及多种异生物质，以及底物选择性 和催化活性的显着影响的结构重排，诱导的结合， SULT辅因子3 '-磷酸腺苷-5'-磷酸硫酸盐。该项目的具体目标是：（1）确定 在人肝细胞模型中控制其转录的SULT 1C 2和1 E1基因的区域 （2）鉴定控制SULT 1C 2和1 E1的转录因子和辅助调节因子 在人肝细胞分化模型和人肝样品中的转录;和（3）表征 人SULT 1C 2的结构-功能活性。该项目将增加我们对以下方面的基本知识： 在人类发育过程中控制内源和外源化学代谢的机制， 发现有关产前表达的主要SULT功能的新信息，并提供 对可能失调SULT表达和功能的环境暴露类型的新见解 在生命中最脆弱的时期