Limits...
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

Sulfated steroids are shuttled across the cell membrane by various OATPs. Different OATPs have differing affinities for different steroids. Once intracellular, steroids can be desulfated by STS, and then resulfated by SULTs. The expression ratio between these competing pathways will, most likely, define ultimate sulfation/desulfation outcome. Sulfated steroids can be removed from the cell via MRP1 and MRP4. Nonsulfated steroids act intracellularly, or, because they are lipid soluble, they will diffuse across the cell membrane and potentially act in a paracrine fashion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4591525&req=5

Figure 4: Sulfated steroids are shuttled across the cell membrane by various OATPs. Different OATPs have differing affinities for different steroids. Once intracellular, steroids can be desulfated by STS, and then resulfated by SULTs. The expression ratio between these competing pathways will, most likely, define ultimate sulfation/desulfation outcome. Sulfated steroids can be removed from the cell via MRP1 and MRP4. Nonsulfated steroids act intracellularly, or, because they are lipid soluble, they will diffuse across the cell membrane and potentially act in a paracrine fashion.

Mentions: Taken together, the relative extent of OATP, MRP, and BCRP tissue expression directly relates to total steroid intracellular concentration, and therefore these transport mechanisms are likely to play key roles in regulating steroid action (Figure 4).


The Regulation of Steroid Action by Sulfation and Desulfation.

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

Sulfated steroids are shuttled across the cell membrane by various OATPs. Different OATPs have differing affinities for different steroids. Once intracellular, steroids can be desulfated by STS, and then resulfated by SULTs. The expression ratio between these competing pathways will, most likely, define ultimate sulfation/desulfation outcome. Sulfated steroids can be removed from the cell via MRP1 and MRP4. Nonsulfated steroids act intracellularly, or, because they are lipid soluble, they will diffuse across the cell membrane and potentially act in a paracrine fashion.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Sulfated steroids are shuttled across the cell membrane by various OATPs. Different OATPs have differing affinities for different steroids. Once intracellular, steroids can be desulfated by STS, and then resulfated by SULTs. The expression ratio between these competing pathways will, most likely, define ultimate sulfation/desulfation outcome. Sulfated steroids can be removed from the cell via MRP1 and MRP4. Nonsulfated steroids act intracellularly, or, because they are lipid soluble, they will diffuse across the cell membrane and potentially act in a paracrine fashion.
Mentions: Taken together, the relative extent of OATP, MRP, and BCRP tissue expression directly relates to total steroid intracellular concentration, and therefore these transport mechanisms are likely to play key roles in regulating steroid action (Figure 4).

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