The Regulation of Steroid Action by Sulfation and Desulfation

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.

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.

Figure 2.

SUMF1 and FGE. SUMF1 encodes for the enzyme FGE, which catalyzes the conversion of cysteine to FGly found at the FGE-recognition site LCTPSR on STS. This reaction results in increased steroid desulfation by elevated STS activity.

Figure 3.

Human sulfation pathways are complex. The various parts of human sulfation pathways are schematically depicted. Several sulfate transporters are responsible for cellular sulfate uptake (reviewed in Refs. and 62), followed by the two-step enzymatic sulfate activation by bifunctional PAPS synthases. PAPS is then either used directly by cytoplasmic and nuclear sulfotransferases or shuttled to the Golgi apparatus to serve a multitude of Golgi-residing carbohydrate and protein sulfotransferases. In contrast to the nonsulfated biomolecules, sulfated xenobiotics or steroids need designated organic anion transporters to enter or exit cells. Many different sulfatases exist to cleave sulfate esters again. The otherwise toxic, sulfation by-product PAP needs to be removed by dedicated phosphatases (reviewed in Ref. 65). In this review, we focus on sulfate activation, steroid sulfation, and desulfation as well as the transport of steroid sulfates via organic anion transporters. For all other steps, the reader may refer to the reviews given above.

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.

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.