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.

胞浆硫转移酶(Sult)结合酶具有代谢内源物质的双重能力 化合物和外源生物，其后果包括加强药物消除，前药物激活， 激素失活和致癌物生物激活。与大多数其他类别的异种代谢不同 酶，有几种酶在产前生命中显著表达，这意味着这些酶执行 在人类发育过程中具有重要的生理功能。另外，尽管母体的肝脏和胎盘 保护胎儿免受外来生物暴露，许多外来物质可以穿过胎盘屏障，使 结果异物暴露对发育过程影响的决定因素尤为重要。 我们的研究小组为人类胚胎发育过程中硫磺的肝脏表达模式提供了新的线索。 发展。例如，我们第一个证明了人类雌激素磺基转移酶(SULT1E1)，一个 主要的雌激素失活酶，在怀孕期间在肝脏中强烈表达，并大幅下调- 在出生后受到监管。然而，控制SULT1E1和其他基因表达的机制 产前表达的结果，如SULT1C2，是未知的。此外，底物的特异性和酶 一些硫磺的发病机制还没有得到充分的定义。在拟议的项目中，我们将确定 在人类肝脏发育过程中控制SULT1C2和1E1表达的机制 为了了解SULT1C2的功能，对SULT1C2进行了详细的酶学研究 在发育中的人类中。我们假设SULT1C2和1E1基因的表达首先上调 随后在人肝细胞分化过程中通过一种协同作用下调 肝脏富集型转录因子网络，其他分化相关转录因子，以及 共同监管机构。我们进一步假设SULT1C2的主要底物包括内源分子 在产前生活中丰富以及多种类型的外源生物，以及底物的选择性 和催化活性受到结构重排的显著影响，这些重排是由结合 结果辅因子3‘-磷酸腺苷-5’-磷酸硫酸盐。这个项目的具体目标是：(1)界定 人肝细胞模型中SULT1C2和1E1基因转录调控区域(S) 分化；(2)确定控制SULT1C2和1E1的转录因子和辅助调节因子 人肝细胞分化模型和人肝标本中的转录；以及(3)表征 人SULT1C2的结构-功能活性。这个项目将增加我们对以下方面的基础知识 在人类发育过程中控制内源性和外源性化学代谢的机制， 发现关于产前表达的主要结果的功能的新信息，并提供 对环境暴露类型的新见解，这些类型可能会扰乱SULT的表达和功能 在这个生命中最脆弱的时期。