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.

胞质磺胺转移酶（SULT）共轭酶具有代谢内源性的双重能力 化合物和异种生物，以及包括增强药物消除，前药激活的后果， 激素失活和促癌生物活化。与大多数其他类异种生物生物代谢不同 酶，在产前生命中显着表达了几种疾病，这意味着这些酶执行 发展中人类的重要生理功能。另外，尽管产妇肝脏和胎盘 保护胎儿免受异种生物的暴露，许多异生物生物可以越过胎盘屏障，使得 苏尔特特别重要的决定因素是异生物暴露对发育过程的影响。 我们的研究小组对人类苏尔特的肝表达模式有了新的启示 发展。例如，我们是第一个表明人雌激素磺胺转移酶（Sult1e1）的人 妊娠期间在肝脏中强烈表达主要的雌激素活化酶 出生后受到监管。但是，控制sult1e1和其他时间表达时间表达的机制 产前表达的苏尔特（例如Sult1c2）尚不清楚。此外，底物特异性和酶促 某些苏尔特的机制没有充分定义。在拟议的项目中，我们将确定 控制人肝发育过程中控制sult1c2和1e1表达的机制，并将表征 详细详细研究Sult1c2的酶学，这是研究最少的研究之一，以了解其功能 在发展中的人类中。我们假设Sult1c2和1e1基因的表达首先上调 随后在人类肝细胞分化过程中通过一个协同的动作下调 富含肝脏的转录因子，其他分化相关的转录因子的网络和 核心节。我们进一步假设Sult1c2的主要底物包括内源分子 在产前寿命以及多种类异生元和底物选择性中丰富 和催化活性显着受结构重排的影响，这些重排是由结合引起的 Sult co-Factor 3'-磷酸腺苷-5'-磷脂。该项目的具体目的是：（1）定义 在人肝细胞模型中控制其转录的Sult1c2和1e1基因的区域 分化； （2）确定控制sult1c2和1e1的转录因子和核心节 人类肝细胞分化和人肝标本模型中的转录； （3）特征 人类Sult1c2的结构功能活性。该项目将增加我们对 控制人类发展过程中内源和外国化学代谢的机制， 发现有关在产前生活中表达的主要宗教功能的新信息，并提供 对可能失调的苏尔特表达和功能失调的环境暴露类型的新见解 在这个最脆弱的时期。