Estrogen sulfotransferase (EST) is a phase II metabolic enzyme that sulfoconjugates and inactivates the steroid hormone estrogen. Although much has been learned on the biochemistry, structural biology and pharmacogenetics of EST and related steroid sulfotransferases, the molecular pharmacology and in vivo function of EST and other steroid sulfotransferases remain incompletely understood. The goal of this proposal is to test the hypothesis that EST is a significant extrahepatic conjugation enzyme that regulates tissue estrogen sensitivity, and as such plays a physiological role in local estrogen metabolism and homeostasis. The long-term objective of this study is to understand how variation in EST activity, through either genetic (pharmacogenetics) or environmental factors (drug-drug interaction), might alter tissue estrogen sensitivity under physiological or therapeutic settings. In our preliminary studies, we have generated an EST knockout (KO) mouse which will be used to test our hypothesis. In this proposal, we will pursue the following specific aims:
Specific aim 1 : To test the hypothesis that uterine and placental EST expression prevents fetal estrogen toxicity. This hypothesis is supported by our preliminary finding that female EST KO mice have reduced fertility. In the absence of EST, unmetabolized estrogen may become toxic to the developing fetus or disturb the parturition process. Pharmacological approaches such as the use of estrogen receptor antagonists will be applied to this investigation.
Specific aim 2 : To test the hypothesis that EST plays a physiological role in maintaining cholesterol homeostasis in Leydig cells. We have found that EST KO mouse Leydig cells abnormally accumulate neutral lipids. We will determine if abnormal lipid accumulation in these cells is mediated by the Scavenger Receptor, Class B, Type I (SRBI) and whether it is dependent on estrogen receptor function. Biochemical, molecular biological and genetic approaches will be applied to address this question.
Specific aim 3 : To test the hypothesis that EST protects Leydig cells from estrogen-induced inhibition of steroidogenesis and that such inhibition occurs either at the substrate mobilization step or at the P450 17a-hydroxylase step.
Specific aim 4 : To test the hypothesis that EST is expressed in the accessory structures of the male reproductive tract in an androgen-dependent manner. Both hypotheses in Specific aim 3 and 4 are supported by our preliminary study of the EST KO mice. The proposed studies will provide a molecular basis for understanding the in vivo pharmacology and physiology of estrogen sulfotransferase as a prototypical phase II steroid sulfoconjugation enzyme.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD042767-01
Application #
6533452
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Yoshinaga, Koji
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$313,065
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Khor, Victor K; Tong, Ming Han; Qian, Yueming et al. (2008) Gender-specific expression and mechanism of regulation of estrogen sulfotransferase in adipose tissues of the mouse. Endocrinology 149:5440-8
Gong, Haibiao; Guo, Ping; Zhai, Yonggong et al. (2007) Estrogen deprivation and inhibition of breast cancer growth in vivo through activation of the orphan nuclear receptor liver X receptor. Mol Endocrinol 21:1781-90
Tong, Ming Han; Jiang, Hong; Liu, Ping et al. (2005) Spontaneous fetal loss caused by placental thrombosis in estrogen sulfotransferase-deficient mice. Nat Med 11:153-9
Tong, M H; Christenson, L K; Song, W-C (2004) Aberrant cholesterol transport and impaired steroidogenesis in Leydig cells lacking estrogen sulfotransferase. Endocrinology 145:2487-97