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

胞质磺基转移酶 (SULT) 结合酶具有代谢内源性物质的双重能力 化合物和异生素，其后果包括增强药物消除、前药激活、 激素失活和促致癌物生物激活。与大多数其他类别的异生素代谢不同 酶，一些 SULT 在产前期间显着表达，这意味着这些酶发挥作用 人类发育过程中重要的生理功能。另外，虽然母体的肝脏和胎盘 保护胎儿免受外源性物质的影响，许多外源性物质可以穿过胎盘屏障，使 SULT 是异生素暴露对发育过程影响的特别重要的决定因素。 我们的研究小组对人类肝脏中 SULT 的表达模式有了新的认识 发展。例如，我们第一个证明人类雌激素磺基转移酶（SULT1E1）是一种 主要雌激素失活酶，在妊娠期间在肝脏中强烈表达，并显着下调 出生后进行调节。然而，控制 SULT1E1 和其他蛋白的时间表达的机制 产前表达的 SULT，例如 SULT1C2，尚不清楚。此外，底物特异性和酶促 一些 SULT 的机制没有得到充分定义。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，并将表征 详细介绍 SULT1C2（SULT 中研究最少的一种）的酶学，以了解其功能 在人类的发展过程中。我们假设 SULT1C2 和 1E1 基因的表达首先上调 并随后在人肝细胞分化过程中通过协同作用下调 富含肝脏的转录因子、其他分化相关转录因子的网络，以及 核心调节器。我们进一步假设 SULT1C2 的主要底物包括内源性分子 产前生活中丰富的以及多种外源物质，并且底物选择性 和催化活性明显受到结构重排的影响，结构重排是由结合引起的 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）定义 SULT1C2 和 1E1 基因在人肝细胞模型中控制转录的区域 差异化； (2)鉴定控制SULT1C2和1E1的转录因子和共调节子 人类肝细胞分化模型和人类肝脏标本中的转录； (3) 表征 人类 SULT1C2 的结构功能活性。这个项目将增加我们的基础知识 在人类发育过程中控制内源性和外源性化学代谢的机制， 发现有关产前生活期间表达的主要 SULT 功能的新信息，并提供 对可能导致 SULT 表达和功能失调的环境暴露类型的新见解 在这个人生最脆弱的时期。

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.