A major clinical challenge is the realization that common diseases such as diabetes, atherosclerotic heart disease, and even some cancers that used to be considered as adult-onset pathologies may actually have their origins during early periods of human development. The cytosolic sulfotransferases (SULTs) catalyze the conjugation of pharmaceuticals, environmental chemicals, hormones, cholesterol, and bile acids. Our long term goal is to understand how differences in SULT1C expression during the stages of development might impact drug efficacy and safety as well as susceptibility to environmental carcinogens and modulators of metabolic processes. Our short-term goals are to determine the expression pattern and regulators of SULT1C expression and to elucidate substrates and inhibitors of SULT1C metabolism. Unlike other xenobiotic- metabolizing enzymes, SULT1Cs are predominantly expressed during fetal life and are known to bioactivate xenobiotic molecules to toxic and carcinogenic intermediates. However, the role(s) of the SULT1C enzymes in endogenous metabolism and physiology are, as yet, uncharacterized. Our discovery that SULT1C genes are regulated by lipid- and xenobiotic-sensing transcription factors defines an unforeseen role for SULT1C enzymes at the heart of human development and metabolic signaling while also indicating that SULT1C enzymes operate at the interface of the physiological and xenobiotic environments. The hypothesis is that (1) the human SULT1C genes are differentially expressed in liver, kidney, stomach, and intestine and during development, (2) expression of these SULTs is differentially regulated by nuclear signaling mechanisms that include the farnesoid X receptor (FXR), the liver X receptor (LXR), the vitamin D receptor (VDR), peroxisome proliferator-activated receptor ? (PPAR?), and the xenobiotic-sensing receptors pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR), and (3) certain sterols and/or bile acids are endogenous substrates for the SULT1C enzymes. To test this hypothesis, the four specific aims of this proposal are to, (1) Determine the expression of human SULT1C2, SULT1C3, and SULT1C4 in fetal, infant, and adult tissue from liver, kidney, stomach, and intestine, (2) Define the mechanisms that control transcription of human SULT1C2, SULT1C3, and SULT1C4 in cellular models of liver, kidney, and intestine, with emphasis on regulation by lipid- and xenobiotic-sensing transcription factors, (3) Define the mechanism(s) that regulate SULT1C2 transcription during hepatic differentiation, and (4) Identify the structure-function activity and inhibition relationships of the human SULT1C enzymes. This project will shed new light on human SULT1C gene expression, regulation, and function. It is essential to obtain this understanding since the SULT1C enzymes likely play important physiological roles during development and, due to their distinct abilities to bioactivat toxic and carcinogenic compounds, are primed to promote disease susceptibility during critical windows of vulnerability.
Sulfotransferase 1C (SULT1C) enzymes are predominantly expressed during fetal life and are known to metabolize hormones and bioactivate carcinogens to harmful DNA damaging species. We have discovered that SULT1C genes are regulated by lipid- and xenobiotic-sensing transcription factors suggesting that SULT1C enzymes operate at the heart of metabolic signaling during human development. The proposed work addresses a significant gap in current knowledge about detoxication defenses and metabolism during fetal life. This research takes aim at the urgent need to protect the developing human from environmental exposures that can damage or reprogram tissues during critical windows of susceptibility that set the stage for disease development later in life.
|Rondini, Elizabeth A; Fang, Hailin; Runge-Morris, Melissa et al. (2014) Regulation of human cytosolic sulfotransferases 1C2 and 1C3 by nuclear signaling pathways in LS180 colorectal adenocarcinoma cells. Drug Metab Dispos 42:361-8|
|Duniec-Dmuchowski, Zofia; Rondini, Elizabeth A; Tibbs, Zachary E et al. (2014) Expression of the orphan cytosolic sulfotransferase SULT1C3 in human intestine: characterization of the transcript variant and implications for function. Drug Metab Dispos 42:352-60|