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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

A, The balance between sulfation and desulfation strongly influences steroid hormone action. The nonsulfated steroid may exert its biological effect by binding to its cognate nuclear receptor or may be downstream converted to more active steroids. Once sulfation occurs by one of various sulfotransferases, solubility of the steroid is dramatically increased, facilitating renal excretion, but also circulatory transit fueling peripheral desulfation and local steroidogenesis. Sulfation may also suppress or modify downstream conversion by masking one of several functional groups; further sulfation steps may occur or sulfated steroids may exert biological effects directly. B, Dysregulation of sulfation and desulfation pathways dramatically alters available active steroids. In disease, especially in cancer, SULT enzymes expression and thus activity are decreased, whereas STS activity is elevated. This situation favors desulfation and therefore results in an elevated local synthesis of active steroids. Furthermore, OATP expression is also elevated in many cancers, increasing the intracellular availability of sulfated steroids to STS action.
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Figure 5: A, The balance between sulfation and desulfation strongly influences steroid hormone action. The nonsulfated steroid may exert its biological effect by binding to its cognate nuclear receptor or may be downstream converted to more active steroids. Once sulfation occurs by one of various sulfotransferases, solubility of the steroid is dramatically increased, facilitating renal excretion, but also circulatory transit fueling peripheral desulfation and local steroidogenesis. Sulfation may also suppress or modify downstream conversion by masking one of several functional groups; further sulfation steps may occur or sulfated steroids may exert biological effects directly. B, Dysregulation of sulfation and desulfation pathways dramatically alters available active steroids. In disease, especially in cancer, SULT enzymes expression and thus activity are decreased, whereas STS activity is elevated. This situation favors desulfation and therefore results in an elevated local synthesis of active steroids. Furthermore, OATP expression is also elevated in many cancers, increasing the intracellular availability of sulfated steroids to STS action.

Mentions: Steroid metabolism is significantly altered in many endocrine-related cancers (269). Evidence suggests that sulfation pathways are down-regulated, whereas STS activity increases in many tumors, thus favoring desulfation and therefore downstream conversion of steroids into more active metabolites (Figure 5).


The Regulation of Steroid Action by Sulfation and Desulfation.

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

A, The balance between sulfation and desulfation strongly influences steroid hormone action. The nonsulfated steroid may exert its biological effect by binding to its cognate nuclear receptor or may be downstream converted to more active steroids. Once sulfation occurs by one of various sulfotransferases, solubility of the steroid is dramatically increased, facilitating renal excretion, but also circulatory transit fueling peripheral desulfation and local steroidogenesis. Sulfation may also suppress or modify downstream conversion by masking one of several functional groups; further sulfation steps may occur or sulfated steroids may exert biological effects directly. B, Dysregulation of sulfation and desulfation pathways dramatically alters available active steroids. In disease, especially in cancer, SULT enzymes expression and thus activity are decreased, whereas STS activity is elevated. This situation favors desulfation and therefore results in an elevated local synthesis of active steroids. Furthermore, OATP expression is also elevated in many cancers, increasing the intracellular availability of sulfated steroids to STS action.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: A, The balance between sulfation and desulfation strongly influences steroid hormone action. The nonsulfated steroid may exert its biological effect by binding to its cognate nuclear receptor or may be downstream converted to more active steroids. Once sulfation occurs by one of various sulfotransferases, solubility of the steroid is dramatically increased, facilitating renal excretion, but also circulatory transit fueling peripheral desulfation and local steroidogenesis. Sulfation may also suppress or modify downstream conversion by masking one of several functional groups; further sulfation steps may occur or sulfated steroids may exert biological effects directly. B, Dysregulation of sulfation and desulfation pathways dramatically alters available active steroids. In disease, especially in cancer, SULT enzymes expression and thus activity are decreased, whereas STS activity is elevated. This situation favors desulfation and therefore results in an elevated local synthesis of active steroids. Furthermore, OATP expression is also elevated in many cancers, increasing the intracellular availability of sulfated steroids to STS action.
Mentions: Steroid metabolism is significantly altered in many endocrine-related cancers (269). Evidence suggests that sulfation pathways are down-regulated, whereas STS activity increases in many tumors, thus favoring desulfation and therefore downstream conversion of steroids into more active metabolites (Figure 5).

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