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The Regulation of Steroid Action by Sulfation and Desulfation.

Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA - Endocr. Rev. (2015)

Bottom Line: Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function.We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action.Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes, and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

No MeSH data available.


Related in: MedlinePlus

Predominance for steroid sulfation or desulfation in endocrine and selected nonendocrine human tissues. Sulfation pathways dominate in the healthy brain, colon, adrenal, and kidney. The colon and kidney sulfate steroids to expedite excretion. The adrenal synthesizes DHEA, which is subsequently sulfated to increase water solubility and allow circulatory transport. The brain favors sulfation, although this is primarily due to the role of pregnenolone sulfate as a neurosteroid. In the liver, a so-called “futile-loop” of DHEA/DHEAS, E1/E1S, and E2/E2S occurs, as well as other steroids. Because sulfated forms of these steroids persist longer in the circulation due to greater half-lives, this accounts for their higher circulating concentrations compared to their nonsulfated forms. Desulfation, via STS, dominates in the breast, ovary, prostate, testis, placenta (not shown), and uteri (not shown). In breast and ovarian tissue, E1S uptake occurs through OATPs (see Section IV), where it is desulfated by STS to form E1, and subsequently E2 via 17βHSDs. In the prostate and testis, circulating DHEAS can also be transported into the cell via OATPs, desulfated by STS, and then metabolized to androgens such as T and DHT, which can then enter the circulation.
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Figure 1: Predominance for steroid sulfation or desulfation in endocrine and selected nonendocrine human tissues. Sulfation pathways dominate in the healthy brain, colon, adrenal, and kidney. The colon and kidney sulfate steroids to expedite excretion. The adrenal synthesizes DHEA, which is subsequently sulfated to increase water solubility and allow circulatory transport. The brain favors sulfation, although this is primarily due to the role of pregnenolone sulfate as a neurosteroid. In the liver, a so-called “futile-loop” of DHEA/DHEAS, E1/E1S, and E2/E2S occurs, as well as other steroids. Because sulfated forms of these steroids persist longer in the circulation due to greater half-lives, this accounts for their higher circulating concentrations compared to their nonsulfated forms. Desulfation, via STS, dominates in the breast, ovary, prostate, testis, placenta (not shown), and uteri (not shown). In breast and ovarian tissue, E1S uptake occurs through OATPs (see Section IV), where it is desulfated by STS to form E1, and subsequently E2 via 17βHSDs. In the prostate and testis, circulating DHEAS can also be transported into the cell via OATPs, desulfated by STS, and then metabolized to androgens such as T and DHT, which can then enter the circulation.

Mentions: Sulfation and desulfation are vital biological processes that regulate steroidogenesis and thus, steroid hormone action in a variety of tissue (Figure 1). Controlled by two distinct enzyme families, the sulfatases and the sulfotransferases (SULTs), these processes are intimately involved in the hydrolysis and esterification of sulfate groups to alkyl (eg, dehydroepiandrosterone [DHEA]) and aryl (eg, estrone [E1]) steroids. As early as the 1940s, steroids were identified as one of the major classes of biomolecules that could be sulfated (1–3). Chemically, it is possible to attach a sulfate to each and every hydroxyl group of a steroid, and taking into account the astonishing substrate promiscuity of the various sulfotransferase enzymes, many different sulfated steroids are detected analytically in biological samples (4). Historically, sulfated steroids were considered to be metabolic end products because their increased water solubility expedites excretion. However, over the past 20 years, a wealth of research demonstrates that sulfated steroids, such as DHEA sulfate (DHEAS) and E1 sulfate (E1S), can act as circulating reservoirs for the peripheral formation of bioactive hormones. Therefore, an understanding of how sulfation and desulfation processes are regulated and dysregulated provides key insights into physiological and pathophysiological endocrine control. This review examines our current understanding of sulfation and desulfation steroid pathways, including the intracellular influx and efflux of sulfated steroids via the organic anion transporter proteins (see Section IV), the role of these pathways in disease (see Sections V and VI), and the potential to pharmacologically target these pathways for therapeutic gain (see Section VII).


The Regulation of Steroid Action by Sulfation and Desulfation.

Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA - Endocr. Rev. (2015)

Predominance for steroid sulfation or desulfation in endocrine and selected nonendocrine human tissues. Sulfation pathways dominate in the healthy brain, colon, adrenal, and kidney. The colon and kidney sulfate steroids to expedite excretion. The adrenal synthesizes DHEA, which is subsequently sulfated to increase water solubility and allow circulatory transport. The brain favors sulfation, although this is primarily due to the role of pregnenolone sulfate as a neurosteroid. In the liver, a so-called “futile-loop” of DHEA/DHEAS, E1/E1S, and E2/E2S occurs, as well as other steroids. Because sulfated forms of these steroids persist longer in the circulation due to greater half-lives, this accounts for their higher circulating concentrations compared to their nonsulfated forms. Desulfation, via STS, dominates in the breast, ovary, prostate, testis, placenta (not shown), and uteri (not shown). In breast and ovarian tissue, E1S uptake occurs through OATPs (see Section IV), where it is desulfated by STS to form E1, and subsequently E2 via 17βHSDs. In the prostate and testis, circulating DHEAS can also be transported into the cell via OATPs, desulfated by STS, and then metabolized to androgens such as T and DHT, which can then enter the circulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591525&req=5

Figure 1: Predominance for steroid sulfation or desulfation in endocrine and selected nonendocrine human tissues. Sulfation pathways dominate in the healthy brain, colon, adrenal, and kidney. The colon and kidney sulfate steroids to expedite excretion. The adrenal synthesizes DHEA, which is subsequently sulfated to increase water solubility and allow circulatory transport. The brain favors sulfation, although this is primarily due to the role of pregnenolone sulfate as a neurosteroid. In the liver, a so-called “futile-loop” of DHEA/DHEAS, E1/E1S, and E2/E2S occurs, as well as other steroids. Because sulfated forms of these steroids persist longer in the circulation due to greater half-lives, this accounts for their higher circulating concentrations compared to their nonsulfated forms. Desulfation, via STS, dominates in the breast, ovary, prostate, testis, placenta (not shown), and uteri (not shown). In breast and ovarian tissue, E1S uptake occurs through OATPs (see Section IV), where it is desulfated by STS to form E1, and subsequently E2 via 17βHSDs. In the prostate and testis, circulating DHEAS can also be transported into the cell via OATPs, desulfated by STS, and then metabolized to androgens such as T and DHT, which can then enter the circulation.
Mentions: Sulfation and desulfation are vital biological processes that regulate steroidogenesis and thus, steroid hormone action in a variety of tissue (Figure 1). Controlled by two distinct enzyme families, the sulfatases and the sulfotransferases (SULTs), these processes are intimately involved in the hydrolysis and esterification of sulfate groups to alkyl (eg, dehydroepiandrosterone [DHEA]) and aryl (eg, estrone [E1]) steroids. As early as the 1940s, steroids were identified as one of the major classes of biomolecules that could be sulfated (1–3). Chemically, it is possible to attach a sulfate to each and every hydroxyl group of a steroid, and taking into account the astonishing substrate promiscuity of the various sulfotransferase enzymes, many different sulfated steroids are detected analytically in biological samples (4). Historically, sulfated steroids were considered to be metabolic end products because their increased water solubility expedites excretion. However, over the past 20 years, a wealth of research demonstrates that sulfated steroids, such as DHEA sulfate (DHEAS) and E1 sulfate (E1S), can act as circulating reservoirs for the peripheral formation of bioactive hormones. Therefore, an understanding of how sulfation and desulfation processes are regulated and dysregulated provides key insights into physiological and pathophysiological endocrine control. This review examines our current understanding of sulfation and desulfation steroid pathways, including the intracellular influx and efflux of sulfated steroids via the organic anion transporter proteins (see Section IV), the role of these pathways in disease (see Sections V and VI), and the potential to pharmacologically target these pathways for therapeutic gain (see Section VII).

Bottom Line: Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function.We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action.Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes, and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

No MeSH data available.


Related in: MedlinePlus