scholarly journals Metabolism of Dehydroepiandrosterone Sulfate and Estrone-Sulfate by Human Platelets

2012 ◽  
pp. 381-388 ◽  
Author(s):  
A. GARRIDO ◽  
Y. MUÑOZ ◽  
W. SIERRALTA ◽  
L. VALLADARES
Keyword(s):  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Human Platelets ◽  
Steroid Sulfatase ◽  
Organic Anion Transporting Polypeptide ◽  
Estrone Sulfate ◽  
High Affinity ◽  
Sulfatase Activity ◽  
17Β Estradiol ◽  
Estrone Sulphate

The aim of the present research was to study the uptake of DHEAS, and to establish the intracrine capacity of human platelets to produce sex steroid hormones. The DHEAS transport was evaluated through the uptake of [3H]-DHEAS in the presence or absence of different substrates through the organic anion transporting polypeptide (OATP) family. The activity of sulfatase enzyme was evaluated, and the metabolism of DHEAS was measured by the conversion of [3H]-DHEAS to [3H]-androstenedione, [3H]-testosterone, [3H]-estrone and [3H]-17β-estradiol. Results indicated the existence in the plasma membrane of an OATP with high affinity for DHEAS and estrone sulphate (E1S). The platelets showed the capacity to convert DHEAS to active DHEA by the steroid-sulfatase activity. The cells resulted to be a potential site for androgens production, since they have the capacity to produce androstenedione and testosterone; in addition, they reduced [3H]-estrone to [3H]-17β-estradiol. This is the first demonstration that human platelets are able to import DHEAS and E1S using the OATP family and to convert DHEAS to active DHEA, and to transform E1S to 17β-estradiol.

scholarly journals GENETIC ANALYSIS OF MURINE ARYLSULFATASE C AND STEROID SULFATASE

Genetics ◽  
1983 ◽  
Vol 105 (1) ◽  
pp. 191-206
Author(s):  
Berthie M Keinanen ◽  
Katherine Nelson ◽  
William L Daniel ◽  
Jose M Roque
Keyword(s):  
Dehydroepiandrosterone Sulfate ◽  
Biochemical Properties ◽  
Postnatal Period ◽  
Autosomal Gene ◽  
Steroid Sulfatase ◽  
Additive Effects ◽  
Estrone Sulfate ◽  
Sulfatase Activity ◽  
Liver And Kidney ◽  
Tissue Differences

ABSTRACT SWR/J mice possess two- to threefold higher 4-methylumbelliferyl sulfate (4MUS), dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E1S) sulfatase activities in liver and kidney extracts than do A/J mice. These interstrain activity differences are maintained throughout the 6- to 45-day postnatal period. Characteristics of the hepatic activities of SWR/J mice suggest that all three activities reside in the same enzyme. Biochemical properties of the SWR/J and A/J enzyme were not significantly different. Expression of hepatic enzyme activity is subject to regulation by an autosomal locus possessing two alleles with additive effects. Postnuclear E1S- and DHEAS-sulfatase activities are primarily microsomal. Although postnuclear hepatic 4MUS-sulfatase activity is predominantly microsomal, renal activity is primarily nonmicrosomal. Only that portion of 4MUS-sulfatase occurring in cell membranes appears capable of hydrolyzing E1S and DHEAS. The hepatic- and renal-specific subcellular distributions of 4MUS-sulfatase activity may reflect tissue differences in enzyme processing. Renal 4MUS-sulfatase activity is also controlled by an autosomal gene with two alleles having additive effects. Positive correlation between hepatic and renal 4MUS-sulfatase activities indicates that both activities are most likely influenced by the same gene.

scholarly journals Identification of a Novel Human Organic Anion Transporting Polypeptide as a High Affinity Thyroxine Transporter

2002 ◽  
Vol 16 (10) ◽  
pp. 2283-2296 ◽  
Author(s):  
F. Pizzagalli ◽  
B. Hagenbuch ◽  
B. Stieger ◽  
U. Klenk ◽  
G. Folkers ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporting Polypeptide ◽  
High Affinity

scholarly journals Steroid sulfatase deficiency causes cellular senescence and abnormal differentiation by inducing Yippee-like 3 expression in human keratinocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyoung-Seok Baek ◽  
Tae-Uk Kwon ◽  
Sangyun Shin ◽  
Yeo-Jung Kwon ◽  
Young-Jin Chun
Keyword(s):  
Cellular Senescence ◽  
Disease Model ◽  
Human Keratinocytes ◽  
Dehydroepiandrosterone Sulfate ◽  
Steroid Sulfatase ◽  
Cholesterol Sulfate ◽  
Knock Out ◽  
Estrone Sulfate ◽  
Breast And Prostate Cancer ◽  
Related Proteins

AbstractHuman steroid sulfatase (STS) is an enzyme that catalyzes the hydrolysis of dehydroepiandrosterone sulfate (DHEAS), estrone sulfate (E1S), and cholesterol sulfate. Abnormal expression of STS causes several diseases including colorectal, breast, and prostate cancer and refractory skin disease. In particular, accumulation of intracellular cholesterol sulfate by STS deficiency leads to a skin disorder with abnormal keratinization called X-linked ichthyosis (XLI). To determine the detailed mechanisms of XLI, we performed RNA sequencing (RNA-seq) analysis using human keratinocyte HaCaT cells treated with cholesterol and cholesterol sulfate. Of the genes with expression changes greater than 1.5-fold, Yippee-like 3 (YPEL3), a factor expected to affect cell differentiation, was found. Induction of YPEL3 causes permanent growth arrest, cellular senescence, and inhibition of metastasis in normal and tumor cells. In this study, we demonstrate that YPEL3 expression was induced by STS deficiency and, using the CRISPR/Cas9 system, a partial knock-out (STS+/−) cell line was constructed to establish a disease model for XLI studies. Furthermore, we show that increased expression of YPEL3 in STS-deficient cell lines promoted cellular senescence and expression of keratinization-related proteins such as involucrin and loricrin. Our results suggest that upregulation of YPEL3 expression by STS deficiency may play a crucial role in inducing cellular senescence and abnormal differentiation in human keratinocytes.

scholarly journals IDENTIFICATION OF AN AUTOSOMAL LOCUS AFFECTING STEROID SULFATASE ACTIVITY AMONG INBRED STRAINS OF MICE

Genetics ◽  
1983 ◽  
Vol 105 (1) ◽  
pp. 181-189
Author(s):  
Robert P Erickson ◽  
Kenneth Harper ◽  
James M Kramer
Keyword(s):  
Recombinant Inbred ◽  
Recombinant Inbred Lines ◽  
Single Gene ◽  
Dehydroepiandrosterone Sulfate ◽  
Inbred Strains ◽  
Inbred Lines ◽  
Steroid Sulfatase ◽  
Steroidal Hormone ◽  
Inbred Strains Of Mice ◽  
Sulfatase Activity

ABSTRACT We have found an activity variant for testicular and liver steroid sulfatase among inbred strains of mice that is not X-linked. C57BL/6J, SM/J and SWR/J testicular extracts hydrolyze 3H-dehydroepiandrosterone sulfate twice as rapidly as do A/J extracts. The C3H/HeJ and DBA/2J strains were intermediate. The Km values for C57BL/6J and A/J are 2.29 ± 0.10 and 1.01 ± 0.02 μM, respectively. The F1 values in both directions were intermediate, which argues against X-linkage of this trait. F2 values show scattered high-intermediate-low values compatible with assay variation superimposed on the segregation of codominant alleles. When assayed for both testicular and liver steroid sulfatase, nine recombinant inbred lines between A/J and C57BL/6J segregate to near the parental strain values. Thus, this activity variation for steroid sulfatase appears to be determined by a single gene, which is not X-linked. Sex and steroidal hormone differences in liver steroid sulfatase activity were not present in the A/J strain, but females of the C57BL/6J and some recombinant inbred lines had higher levels. Electrophoretic studies only disclosed a variant in the SM/J strain, which seems to be secondary to the well-known neuraminidase variation in SM/J.

scholarly journals Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

2011 ◽  
Vol 212 (2) ◽  
pp. 99-110 ◽  
Author(s):  
Atul Purohit ◽  
Paul A Foster
Keyword(s):  
Clinical Trials ◽  
Dehydroepiandrosterone Sulfate ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Developmental History ◽  
Estrone Sulfate ◽  
Therapy Targets ◽  
History Of

Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

scholarly journals Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

2005 ◽  
Vol 26 (2) ◽  
pp. 171-202 ◽  
Author(s):  
M. J. Reed ◽  
A. Purohit ◽  
L. W. L. Woo ◽  
S. P. Newman ◽  
B. V. L. Potter
Keyword(s):  
Tumor Growth ◽  
Prognostic Significance ◽  
Dehydroepiandrosterone Sulfate ◽  
The Body ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Estrone Sulfate ◽  
Estrogenic Properties ◽  
Hydrolysis Of

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

scholarly journals Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2704-2712 ◽  
Author(s):  
Masatoshi Tomi ◽  
Hiromi Eguchi ◽  
Mayuko Ozaki ◽  
Tomohiro Tawara ◽  
Sachika Nishimura ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Cellular Level ◽  
Organic Anion Transporter ◽  
Organic Anion Transporting Polypeptide ◽  
Anion Transporter ◽  
Basal Plasma ◽  
Good Agreement

Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [3H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [3H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [3H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

scholarly journals Relative contribution of OAT and OCT transporters to organic electrolyte transport in rabbit proximal tubule

2004 ◽  
Vol 287 (5) ◽  
pp. F999-F1010 ◽  
Author(s):  
Xiaohong Zhang ◽  
Carlotta E. Groves ◽  
Andrew Bahn ◽  
Wendy M. Barendt ◽  
Marcos D. Prado ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Cultured Cells ◽  
Organic Anion ◽  
Weak Acid ◽  
Organic Electrolyte ◽  
Weak Base ◽  
Estrone Sulfate ◽  
High Affinity ◽  
Relative Contribution ◽  
Relative Expression Level

We compared the characteristics of several cloned rabbit organic electrolyte (OE) transporters expressed in cultured cells with their behavior in intact rabbit renal proximal tubules (RPT) to determine the contribution of each to basolateral uptake of the weak acid ochratoxin A (OTA) and the weak base cimetidine (CIM). The activity of organic anion transporters OAT1 and OAT3 proved to be distinguishable because OAT1 had a high affinity for PAH ( Ktof 20 μM) and did not support estrone sulfate (ES) transport, whereas OAT3 had a high affinity for ES ( Ktof 4.5 μM) and a weak interaction with PAH (IC50> 1 mM). In contrast, both transporters robustly accumulated OTA. Intact RPT also accumulated OTA, with OAT1 and OAT3 each responsible for ∼50%: ES and PAH each reduced uptake by ∼50%, and the combination of the two eliminated mediated OTA uptake. The weak base CIM was transported by OAT3 ( Ktof 80 μM) and OCT2 ( Ktof 2 μM); OCT1 had a comparatively low affinity for CIM, and CIM uptake by OAT1 was equivocal. Intact RPT accumulated CIM, with TEA and ES reducing CIM uptake by 20 and 75%, respectively, suggesting that OAT3 plays a quantitatively more significant role in CIM uptake in the early proximal tubule than OCT1/2. In single S2 segments of RPT, ES and TEA each blocked ∼50% of CIM uptake. Thus the fractional contribution of different OE transporters to renal secretion is influenced by their affinity for substrate and relative expression level in RPT.

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