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.
The cytoplasmic sulfotransferase (SULT) conjugating enzymes are expressed from the earliest stages of human development and throughout the life-course. The SULTs metabolize both endogenous and foreign chemicals, sometimes to less toxic or inactive compounds and sometimes to reactive and carcinogenic compounds, and so are important determinants of the effects of the environment on the human during critical early windows of susceptibility that can program an individual?s likelihood of developing disease later in life. SULT expression varies markedly among individuals and changes over time, but the mechanisms that control these dynamic changes in metabolic capability are not understood. This project will undertake the challenge of developing a comprehensive and detailed understanding of the mechanisms that control SULT expression and function during human development.
