Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenols are used world-wide and their presence in the environment is a cause of increasing concern. Despite evidence to suggest that, in general, they bind poorly to estrogen receptors, they are suspected of being endocrine disrupters. Here, we show that 2, x-substituted phenols are potent inhibitors of estrogen sulfotransferase with IC(50) values at low- or sub-micromolar levels. Our results demonstrate a potential non-genomic mechanism of action for these compounds and suggest that, where viable alternatives exist, both phenols substituted in the 2-position and their metabolic precursors should be avoided.
Mol Cell Endocrinol 2005 Dec 01
PMID:Non-genomic effects of endocrine disrupters: inhibition of estrogen sulfotransferase by phenols and chlorinated phenols. 1626 79

Cytosolic sulfotransferases (SULTs) are a major family of phase II drug-metabolizing enzymes. SULT-catalyzed sulfonation regulates hormone activities metabolizes drugs detoxifies xenobiotic toxicants bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1 DHEA-ST) plays a very important role in sulfating endogenous hydroxysteroids and exogenousxenobiotics. Our recent studies have shown that methotrexate can induce hSULT2A1 expression. To investigate the molecular mechanism involved in hSULT2A1 induction we generated the promoter sequence of hSULT2A1 by PCR and constructed a reporter gene vector. Both reporter gene assay and endogenous induction results suggested that human constitutive active receptor (hCAR) mediates the methotrexate induction of hSULT2A1 in both Caco-2 and Hep G2 cells. Human vitamin D receptor (hVDR) also upregulated hSULT2A1 gene expression while human pregnane X receptor (hPXR) downregulated it. Human pregnane X receptor suppressed hCAR-mediated methotrexate induction of hSULT2A1 in both Caco-2 and Hep G2 cells. hVDR competed with hCAR for the hSULT2A1 promoter in Caco-2 cells. hCAR inhibited hVDR-mediated vitamin D3 induction of hSULT2A1 but not methotrexate induction of hSULT2A1. These results strongly support the hypothesis that cross-talk occurs among nuclear receptors in the signal transduction pathway of hSULT2A1 and that interactions among nuclear receptors also depend on ligands (inducers) in the system.
J Biochem Mol Toxicol 2006
PMID:Nuclear receptor interactions in methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1). 1716 85

Spontaneous canine mammary inflammatory carcinoma (IMC) shares epidemiologic, histopathologic and clinical characteristics with the inflammatory breast carcinoma (IBC) disease in humans. We have analysed the steroids levels in serum and in tissue homogenates of IMC, the expression of two of their receptors (androgen and beta-estrogen) and of three enzymes included in the steroidogenesis pathway (aromatase (CYP19A1), steroid sulphatase (STS) and estrogen sulfotransferase (EST)) trying to explain the specific accumulation of steroids in IMC tissues generating deposits in the form of lipid droplets whose presence can be attributed to steroids secreted by IMC cells. According to our working hypothesis, oestrone sulphate would be the main component of these lipid droplets. The presence of these steroid deposits would contribute to the intense proliferation and invasive behaviour of IMC and IBC, although their involvement in angiogenesis is yet to be demonstrated.
J Steroid Biochem Mol Biol 2007 May
PMID:Steroid pathway and oestrone sulphate production in canine inflammatory mammary carcinoma. 1746 17

Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer, and antiestrogen therapies have been shown to be effective in the treatment and prevention of breast cancers. The liver is important for estrogen metabolism, and a compromised liver function has been linked to hyperestrogenism in patients. In this report, we showed that the liver X receptor (LXR) controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est, or Sult1e1), an enzyme critical for metabolic estrogen deactivation. Genetic or pharmacological activation of LXR resulted in Est induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est is a transcriptional target of LXR, and deletion of the Est gene in mice abolished the LXR effect on estrogen deprivation. Interestingly, Est regulation by LXR appeared to be liver specific, further underscoring the role of liver in estrogen metabolism. Activation of LXR failed to induce other major estrogen-metabolizing enzymes, suggesting that the LXR effect on estrogen metabolism is Est specific. In summary, our results have revealed a novel mechanism controlling estrogen homeostasis in vivo and may have implications for drug development in the treatment of breast cancer and other estrogen-related cancerous endocrine disorders.
Mol Endocrinol 2007 Aug
PMID:Estrogen deprivation and inhibition of breast cancer growth in vivo through activation of the orphan nuclear receptor liver X receptor. 1753 9

Intratumoral metabolism and synthesis of biologically active steroids such as estradiol and 5alpha-dihydrotestosterone as a result of interactions of various enzymes are considered to play very important roles in the pathogenesis and development of hormone-dependent breast carcinoma. Among these enzymes involved in estrogen metabolism, intratumoral aromatase play an important role in converting androgens to estrogens in situ from serum and serving as the source of estrogens, especially in postmenopausal patients with breast carcinoma. However, other enzymes such as 17beta-hydroxysteroid dehydrogenase (17beta-HSD) isozymes, estrogen sulfatase (STS), and estrogen sulfotransferase, which contribute to in situ availability of biologically active estrogens, also play pivotal roles in this intratumoral estrogen production above. Androgen action on human breast carcinoma has not been well-studied but are considered important not only in hormonal regulation but also other biological features of carcinoma cells. Intracrine mechanisms also play important roles in androgen actions on human breast carcinoma cells. Among the enzymes involved in biologically active androgen metabolism and/or synthesis, both 17beta-hydroxysteroid dehydrogenase type 5 (17betaHSD5; conversion from circulating androstenedione to testosterone) and 5alpha-reductase (5alphaRed; reduction of testosterone to DHT (5alpha-dihydrotestosterone) were expressed in breast carcinoma tissues, and in situ production of DHT has been proposed in human breast cancer tissues. However, intracrine mechanisms of androgens as well as their biological or clinical significance in the patients with breast cancer have not been fully elucidated in contrast to those in estrogens.
J Steroid Biochem Mol Biol 2008 Feb
PMID:Intracrinology of estrogens and androgens in breast carcinoma. 1793 21

The aim of the present investigation was to study whether the endocrinological status of women bearing polycystic ovarian syndrome (PCOS) affects the endometrial in situ steroid metabolism. For this purpose, we evaluated the mRNA levels (RT-PCR), and the activity of steroid metabolic enzymes: P450 aromatase, steroid sulfatase (STS), estrogen sulfotransferase (EST) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in 23 samples of normal endometria (CE), 18 PCOS endometria without treatment (PCOSE), 10 specimens from PCOS women with endometrial hyperplasia (HPCOSE), and 7 endometria from patients with endometrial hyperplasia not associated to PCOS (EH). The data showed lower levels of STS mRNA for PCOSE and HPCOSE (p<0.05, p<0.01, respectively) and of EST for HPCOSE and EH compared to control (p<0.05). However, higher levels for EST mRNA were obtained in PCOSE (p<0.05) versus CE. The mRNA and protein levels for P450 aromatase were undetectable in all analyzed endometria. The relationship between the activities of STS and EST was lower in PCOSE and HPCOSE (p<0.05) versus CE. The ratio between the mRNA from 17beta-HSD type 1/type 2 was higher in PCOSE (p<0.05), whereas, a diminution in the 17beta-HSD type 2 activity was observed in PCOSE (p<0.05). These results indicate that the activity of enzymes related to the steroid metabolism in analyzed PCOSE differ from those found in the CE. Consequently, PCOSE may present an in situ deregulation of the steroid metabolism.
J Steroid Biochem Mol Biol 2008 May
PMID:In situ estrogen metabolism in proliferative endometria from untreated women with polycystic ovarian syndrome with and without endometrial hyperplasia. 1846 89

Sex steroids, including those through intratumoral production in an intracrine manner, play important roles in the development of invasive ductal carcinoma (IDC) of human breast, but biological and/or clinical significance of intratumoral production and metabolism of sex steroids, have remained largely unknown in the ductal carcinoma in situ (DCIS), an important precursor lesion of IDC. We recently examined tissue concentration of estradiol and 5-dihydrotestosterone using liquid chromatography/electrospray tandem mass spectrometry in non-neoplastic breast, DCIS, and IDC tissues. Results of our study suggest that intratumoral concentrations of both estradiol and 5-dihydrotestosterone are increased in DCIS, which is considered due to intratumoral production of these sex steroids. Therefore, both estradiol and 5-dehydrotestosterone are considered to play important roles in the development of DCIS as well as IDC through an intracrine manner. Intratumoral metabolism and synthesis of estrogens and androgens as a result of the interactions of various enzymes are therefore also considered to play important roles in hormone dependent DCIS. Aromatase, which is one of the estrogen synthesis enzymes, plays an important role in intratumoral production of estrogen but other enzymes also play pivotal roles in intratumoral estrogen and androgen productions in human breast carcinoma. Therefore, in this review, we also focused on the importance of key intracrine enzymes such as 17beta-hydroxysteroid dehydrogenases, steroid sulfatase,estrogen sulfotransferase, 5alpha-reductases in both IDC and DCIS.
J Steroid Biochem Mol Biol 2009 Mar
PMID:Intracrinology of sex steroids in ductal carcinoma in situ (DCIS) of human breast: comparison to invasive ductal carcinoma (IDC) and non-neoplastic breast. 1944 35

It is well established that various endocrine disrupting compounds (EDCs) can inhibit human estrogen sulfotransferase (SULT1E1). In this study, we investigate murine SULT1E1 inhibition in vitro and in silico and compare this to data for the human enzyme. 34 potential EDCs were screened for their ability to inhibit both murine and human SULT1E1 and IC(50) values were determined for 14 of the inhibitory EDCs. Only estrone, dienestrol and enterolactone showed significant differences in affinity between the human and murine SULT1E1. Extensive molecular modelling was performed using molecular dynamics (MD) simulations. During the MD simulations the ligands moved away from the catalytically active position, something which was not observed when simulating the unit cell of the crystal structure. This finding suggests that catalytically inactive binding modes, other than the one observed in the crystal structures, are possible in SULT1E1. The ligands stayed longer in the catalytically active position in mSULT1E1, which is likely a result of simultaneous hydrogen bond formation on both sides of the binding pocket, which does not seem to be possible in hSULT1E1. The ligands in the human protein moved to a sub-pocket near the entrance of the active site, which offers hydrogen bond formation possibilities with Asp22 and Lys85 as well as favourable hydrophobic interactions. The ligands moved more randomly in mSULT1E1. These observations offer a possible explanation for the substrate inhibition only observed in hSULT1E1.
Mol Cell Endocrinol 2010 Apr 12
PMID:Comparison of murine and human estrogen sulfotransferase inhibition in vitro and in silico--implications for differences in activity, subunit dimerization and substrate inhibition. 2002 31

Biochanin A (BCA) is a dietary isoflavone present in red clover (Trifoliumn pretense) and many herbal products. BCA has been reported to have chemopreventive actions against various cancers including prostate, breast, colon cancer, and so on. Sulfotransferases are a family of phase II drug-metabolizing enzymes, which are important for xenobiotic detoxification and regulation of biological signaling molecule biological activities. Sulfotransferase gene expressions are regulated by different hormones and xenobiotics. Improper regulation of sulfotransferases leads to improper functions of biological signaling molecules, which in turn can cause cancer or other diseases. BCA inhibits the enzyme activities of the phase I drug-metabolizing enzymes CYP1A1 and CYP1B1 in Chinese hamster ovary cells and induces the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases in human prostate cancer cells. BCA induction of sulfotransferases has not been studied. This investigation evaluates the in vivo regulation of sulfotransferases at protein and mRNA levels in the liver and intestine of Sprague-Dawley rats treated with BCA (0, 2, 10, and 50 mg/kg/day) for 7 days. Our experimental results demonstrate for the first time that chronic BCA treatment can significantly induce the expression of rat sulfotransferase 1A1 (rSULT1A1, AST-IV), sulfotransferase 2A1 (rSULT2A1, STa), and rat estrogen sulfotransferase (rSULT1E1, EST) in rat liver and intestine. Our Western blot results are in good agreement with real-time RT-PCR data, suggesting that BCA induction of sulfotransferases occurs at the transcriptional level.
J Biochem Mol Toxicol
PMID:Biochanin A induction of sulfotransferases in rats. 2039 25

Estrogens are closely involved in the development of hormone-dependent carcinomas. Estrone is locally produced from circulating inactive estrone sulfate by steroid sulfatase (STS), while estrone is inversely inactivated into estrone sulfate by estrogen sulfotransferase (EST). Recent studies suggested importance of this STS pathway in various human carcinomas. Therefore, in this review, we summarized recent results of STS and EST in several estrogen-dependent carcinomas. STS and EST expressions were detected in the breast and endometrial carcinomas, and activation of STS pathway due to increment in STS and/or decrement in EST expressions plays important role in their estrogen-dependent growth. STS expression was also reported in the ovarian and prostate carcinomas. STS/EST status was associated with intratumoral estrogen level in the colon carcinoma, and STS-negative/EST-positive colon carcinoma patients had longer survival. Therefore, STS pathway and estrogen actions may play an important role in the development of these carcinomas, and further investigations are required.
Mol Cell Endocrinol 2011 Jul 04
PMID:Steroid sulfatase and estrogen sulfotransferase in human carcinomas. 2107 15


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