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Center for Experimental Therapeutics and Department of Pharmacology, and Center for Research on Reproduction and Women’s Health (W.-C.S.) University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104 E-mail: Song@spirit.gcrc.upenn.edu and Departments of Obstetrics & Gynecology and Cell Biology (M.H.M.) Vanderbilt University School of Medicine Nashville, Tennessee 37232 E-mail: mike.melner@mcmail.vanderbilt.edu
Address all correspondence and requests for reprints to: Dr. Michael H. Melner, Ph.D., Departments of Obstetrics & Gynecology and Cell Biology, Vanderbilt University School of Medicine, B1100 Medical Center North, 1161 21st Avenue, South Nashville, Tennessee 37232. E-mail: mike.melner{at}mcmail.vanderbilt.edu
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Introduction |
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 Top Introduction References |
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The concept that steroid modifying enzymes such as EST have critical
physiological roles in modifying steroid hormone action at target cells
has been emerging based upon multiple studies in different systems (2, 3). In some systems, the enzymes cause a selectivity of receptor
binding by eliminating competing steroids. For example, the selectivity
of mineralocorticoids for the mineralocorticoid receptor is not due to
any inherent differences in binding affinities between cortisol and
aldosterone but instead due to the action of 11ß-hydroxysteroid
dehydrogenase (type II isozyme) at inactivating cortisol (4). If the
activity of 11ß-HSD is inhibited pharmacologically, cortisol is
present in target cells and subsequently binds to the mineralocorticoid
receptor eliciting an effective response. In other systems, the
inactivation of steroid hormones at the target cells yields an
appropriate physiological response. An example of this was shown by
targeted disruption of the 5
-reductase type 1 gene in mice. A
majority of the female mice with knockout of the 5-reductase type 1
gene have a parturition defect and fail to deliver their litters. The
mechanisms underlying this defect indicate that altered metabolism of
progesterone in the cervix impairs normal cervical ripening important
for parturition (5, 6). The current studies of EST and its expression
in estrogen target tissues are further evidence suggesting that
modifications of the activities of these enzymes affect estrogen
action. The list of enzymes that may act to modify steroid action is
growing. The 20-hydroxysteroid dehydrogenase enzyme is expressed in
the corpus luteum, a tissue known to be both a site of progesterone
synthesis and a progesterone target tissue, specifically during
luteolysis (7). Another enzyme involved in the inactivation of steroid
hormones is UDP glucuronosyltransferase, which catalyzes
glucuronidation of the 3-hydroxyl group of estrogens and androgens (8).
While this enzyme is known to be expressed in the liver, the surprising
finding has been that this enzyme is expressed in many estrogen and
androgen target tissues including the mammary gland, ovary, prostate,
testis, and epididymis (8). Thus, it will be of interest to follow
future studies to determine whether these enzymes can modify steroid
hormone action and whether their activities are regulated under
physiological, pathological, or pharmacological influences.
Estrogen sulfotransferase belongs to the family of cytosolic sulfotransferases (9). It catalyzes the transfer of a sulfonate radical (SO3-) to the 3-hydroxyl group of estrogens using 3'-phosphoadenosine-5'-phosphosulfate as a donor for the SO3- group. The cytosolic sulfotransferases in general are best recognized as phase II metabolic enzymes in the liver that help the body eliminate xenobiotic metabolites by increasing their polarity and water solubility through sulfoconjugation. They are considered as low capacity enzymes that use as their substrates small molecules of both endogenous and exogenous origins such as steroids, drugs, and xenobiotic chemicals. In this regard they are distinct from another class of sulfotransferases that are membrane-bound and use macromolecules such as proteins, proteoglycans, and glycosaminoglycans as their preferred substrates (9). It has been recognized for decades that steroid hormones are natural substrates of cytosolic sulfotransferases. Indeed, in some species, steroid sulfates actually circulate in the blood at levels exceeding that of the parent steroid hormones (9, 10). This has raised the question as to whether steroid sulfates are produced merely for the purpose of excretion (9, 10). Regardless of its net effect on systemic steroid hormone homeostasis, it is well accepted that sulfonation diminishes the receptor-binding activity of a steroid hormone and renders it biologically inactive (9, 10, 11).
Rapid progress has been made in the last decade concerning the molecular characterization of steroid sulfotransferases. In mammalian species there are two distinct steroid sulfotransferases. One prefers hydroxysteroids such as dehydroepiandrosterone and pregnenolone as its substrates (hydroxysteroid sulfotransferase or HSST) and the other, EST with high substrate specificity for estrogens (9). Much knowledge has been gained regarding the structure of EST through x-ray crystallography studies of the recombinant mouse form (12, 13). With the availability of appropriate reagents (complementary DNAs, antibodies) and techniques (e.g. transgenic and gene knockout mouse), the physiological role of EST has become amenable to investigation in animal models (14, 15). One of the striking characteristics of EST is its high substrate specificity. Both the human and the mouse enzyme have been shown to have Km values in the nanomolar range (14, 16, 17). Thus, unlike the cytochrome P450 enzymes that usually require high substrate concentrations to display any catalytic activity, the EST enzyme is expected to react with physiological concentrations of estrogens. A second interesting finding concerning EST is that the enzyme is found to be expressed or induced in several estrogen target tissues such as the mammary epithelial cells (18, 19), the endometrium (20), and the testis (14, 21, 22). This suggests that EST could function as a molecular switch in these tissues to control local estrogen activity. A proof of principle for this concept has been provided by independent cDNA transfecton studies. Transfection of the human or the mouse EST cDNA to MCF-7 cells, an estrogen-dependent breast cancer cell line, significantly reduced the proliferative response of these cells to physiological concentrations of estrogens (19, 23).
The role of EST in modulating estrogen action at target cells is under investigation in multiple systems. One such system is testicular Leydig cells, which not only express abundant EST (14, 21, 22) but are also a source of estrogen synthesis with P450 aromatase expression and a target for estrogen with estrogen receptors (24, 25, 26). Gene knockout mouse studies of estrogen receptors and P450 aromatase have renewed considerable interest in the testicular biology of estrogens (27, 28). The testis is a source for estrogen production, both in animals and in man with the estrogen biosynthetic enzyme P450 aromatase detected in Leydig cells and germ cells of a number of species (24, 25, 29). The estrogen receptor and P450 aromatase gene knockout mice have firmly established that estrogen is required for normal testicular function (27, 28). On the other hand, bioactivity of the locally produced estrogen in the testis may also need to be properly regulated to prevent the deleterious effect of chronic estrogen stimulation. This could well be the principal task performed by the Leydig cell EST. The expression of EST in mouse Leydig cells is controlled by LH and androgen and closely correlates with steroidogenic activity and sexual maturity. Thus, no EST protein or mRNA is detected in the testes of immature, hypophysectomized or androgen-insensitive mice (21, 22). These findings are consistent with the hypothesis that EST plays a physiological role in normal testicular function. The concept that EST acts as a molecular switch to control local estrogen activity in the testis has been validated by the testicular phenotype of EST-deficient mice generated by gene targeting. These mice, among other abnormalities, display Leydig cell dysfunction and seminiferous tubule damage (30; Qian, Y. M., X. Sun, X. P. Li, and W.-C. Song, manuscript submitted).
The finding of Kester et al. (1) in this issue is of special interest in light of our increased appreciation of steroid transformation enzymes as significant regulators of steroid action in target tissues. The possibility that environmental chemicals may act as endocrine disruptors in the body has far reaching implications for human reproductive health and was the subject of an editorial in a previous issue of the journal (32). This is a topic that has received considerable attention both in the popular press and in the scientific field, but uncertainties still abound (33, 34). It is true that many man-made chemicals in our environment such as pesticides, plastic additives, detergents, and other industrial pollutants can interact with the estrogen or androgen receptors and cause either activation or blockade of these nuclear receptors (33). The problem is that many of these chemicals that have been suspected to disrupt normal endocrine functions interact only weakly, if at all, with the estrogen or androgen receptor (35, 36, 37). For example, Bisphenol-A (BPA), one of the well-characterized xenoestrogens, is estimated to be 1,000- to 5,000- fold less potent in vitro than the endogenously produced estradiol (38). Thus, one may ask the legitimate question whether exposure to low levels of these chemicals matters in view of the fact that much more potent endogenous estrogens are circulating in the reproductive tissues of animals and man? The paper by Kester et al. (1) provides a novel and refreshing perspective to this paradoxical question. The potency demonstrated for some of the OH-PCBs as noncompetitive inhibitors of estrogen sulfotransfearse is truly remarkable (1). This finding raises the possibility that an environmental chemical does not have to interact with the estrogen receptor itself to be estrogenic in vivo. By inhibiting EST activity, an endocrine disrupting chemical can increase the bioavailability of endogenous estrogen in target tissues. This could produce deleterious effects due to excessive estrogen stimulation.
The in vitro study by Kester et al. (1) is only the first step toward understanding the endocrine disrupting potential of PCBs. The in vivo pharmacology of PCB is undoubtedly more complex due to bioavailability issues (metabolism, transport across the cell membrane, competitive binding to other proteins, etc.), and it remains to be determined if the extraordinary efficacy of OH-PCBs as EST inhibitors demonstrated in vitro can be extended to in vivo models. Nevertheless, it has raised the question as to whether other steroid transformation enzymes might also be targets of inhibition by PCBs or other environmental chemicals. As far as EST is concerned, there may be other mechanisms by which environmental chemicals function as estrogenic endocrine disruptors in vivo. For example, by being a poor substrate for EST inactivation, a known xenoestrogen may display a higher relative activity in vivo than in vitro. Secondly, because EST expression both in the liver and in the testis is regulated by androgen in a receptor-dependent manner (15, 22), environmental chemicals such as vinclozolin with antiandrogenic activity (37) may also become estrogenic by inhibiting EST gene expression. Hopefully, the report by Kester et al. (1) will serve as a catalyst to stimulate new and innovative research on this important topic of reproductive endocrinology.
Received March 7, 2000.
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References |
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TopIntroductionReferences |
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-reductase type I caused by estrogen
excess. Mol Endocrinol 11:917–927-reductase type I knockout mice
is due to impaired cervical ripening. Mol Endocrinol 13:981–992-hydroxysteroid dehydrogenase
gene expression and the tyrosine kinase system. Biochem Biophys Res
Commun 235:587–592[CrossRef][Medline]
knock-out and wild-type mice. Endocrinology 139:982–2987This article has been cited by other articles:
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  D. J. Waxman and M. G. Holloway Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes Mol. Pharmacol., August 1, 2009; 76(2): 215 - 228. [Abstract] [Full Text] [PDF]
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 J. Balthazart, M. Baillien, and G. F. Ball Rapid Control of Brain Aromatase Activity by Glutamatergic Inputs Endocrinology, January 1, 2006; 147(1): 359 - 366. [Abstract] [Full Text] [PDF]
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M. H. Tong, L. K. Christenson, and W.-C. Song Aberrant Cholesterol Transport and Impaired Steroidogenesis in Leydig Cells Lacking Estrogen Sulfotransferase Endocrinology, May 1, 2004; 145(5): 2487 - 2497. [Abstract] [Full Text] [PDF]
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 M. H. A. Kester, S. Bulduk, H. van Toor, D. Tibboel, W. Meinl, H. Glatt, C. N. Falany, M. W. H. Coughtrie, A. G. Schuur, A. Brouwer, et al. Potent Inhibition of Estrogen Sulfotransferase by Hydroxylated Metabolites of Polyhalogenated Aromatic Hydrocarbons Reveals Alternative Mechanism for Estrogenic Activity of Endocrine Disrupters J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1142 - 1150. [Abstract] [Full Text] [PDF]
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Y. M. Qian, X. J. Sun, M. H. Tong, X. P. Li, J. Richa, and W.-C. Song Targeted Disruption of the Mouse Estrogen Sulfotransferase Gene Reveals a Role of Estrogen Metabolism in Intracrine and Paracrine Estrogen Regulation Endocrinology, December 1, 2001; 142(12): 5342 - 5350. [Abstract] [Full Text] [PDF]
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H. W. Woitge, J. R. Harrison, A. Ivkosic, Z. Krozowski, and B. E. Kream Cloning and in Vitro Characterization of {{alpha}}1(I)-Collagen 11{{beta}}-Hydroxysteroid Dehydrogenase Type 2 Transgenes as Models for Osteoblast-Selective Inactivation of Natural Glucocorticoids Endocrinology, March 1, 2001; 142(3): 1341 - 1348. [Abstract] [Full Text] [PDF]
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