The overall goal of this project is to investigate the biochemistry and molecular biology of the human cytosolic sulfotransferases (STs) and to understand the role of sulfation in the metabolism of drugs, xenobiotics and endogenous substrates in normal and cancerous human tissues. Sulfation is involved in the metabolism and regulation of activity of many endogenous compounds including steroid and thyroid hormones, monoamine neurotransmitters, vitamins, and bile acids. The sulfation of steroid hormones is important in the regulation of hormonal activity in human tissues. Steroid sulfates are inactive because steroid sulfates do not bind to their receptors and initiate a cellular response. At least six human STs can sulfate estrogenic compounds; however, because of its high affinity for beta- estradiol (E2), estrogen ST (EST, SULT1E1) is the ST involved in inactivating estrogens in estrogen responsive tissues such as endometrium and breast. During the previous funding periods of this grant, the number of identified human cytosolic STs has increased to ten. Little is known as to the protein chemistry or molecular biology of these newly identified forms of ST. Even less is known about the physiological functions of the ST isoforms. We believe that this fundamental biochemical information will improve our understanding of human drug metabolism and provide information for drug design and therapy as well as increase our knowledge of the functions of sulfation in cellular physiology. We have also identified a novel form of human ST-like protein, BR-STL, selectively expressed in human brain tissues. Thus, this proposal focuses on the investigation of the role of the STs in regulating estrogen responsiveness of normal and cancerous breast cells, as well as on the characterization of three novel human cytosolic STs which have been recently identified.
The Specific Aims of this proposal are: 1) to analyze the expression and role of EST and the PSTs in regulating estrogenic activity in human normal and cancerous breast tissue and 2) to characterize the properties and functions of the recently described human STs, ST2B1a, ST2B1b and ST1C1, and the ST-like protein BR-STL.
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