The overall goal of this project is to investigate the biochemistry and physiological functions of the human cytosolic sulfotransferases (SULTs). The cytosolic SULTs are responsible for the sulfation of many drugs and xenobiotics and thereby play a major role in Phase 2 metabolism and excretion. Additionally, many of the SULTs are involved in the metabolism of endogenous compounds including monoamine neurotransmitters as well as steroid and thyroid hormones. Steroid sulfates are biologically inactive since they do not bind and activate their appropriate receptors. Humans are relatively unique in steroid hormone synthesis and metabolism due to the high levels of adrenal androgens synthesized after adrenarche as well as the high levels of adrenal androgens and estrogens synthesized during fetal development. In humans, most adrenal androgens and estrogens circulate as sulfate esters and provide a reservoir for active steroids following the removal of the sulfate group by sulfatase activity. The steroids can then be converted to different potentially active forms in target tissues. The presence of the sulfate moiety inhibits the further metabolism of the steroids. In this proposal, we will focus on the characterization of biochemical, molecular and functional properties of the three major human steroid SULTs: (1) SULT1E1 which is responsible for the high affinity and regulation of activity of estrogens, (2) SULT2A1 which is involved in the synthesis and secretion of DHEA-sulfate in the adrenal, and (3) SULT2B1b, a recently described isoform selective for the sulfation of 3beta-hydroxysteroids. We hypothesize that the tissue specific expression of these SULTs in normal and diseased hormone-responsive tissues will have important effects on the activity and synthesis of steroids within those tissues. The following specific aims are proposed: (1) to investigate the role of steroid sulfation in the regulation of human prostate tissue responsiveness, (2) to investigate the subcellular localization of SULT2B1b in human placental and breast cells, and (3) to investigate the role of specific single nucleotide polymorphisms in the SULT2A1 gene unique to African-Americans on DHEA and DHEA-sulfate synthesis.
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