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The Role of Steroid Sulfatase and Sulfotransferase Enzymes in the Metabolism of C21 and Cl9 Steroids
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
Considerable interest in the biological role of steroid sulfates has developed during the past decade. It is now well accepted that steroid sulfates are not merely end products of metabolism whose only fate is removal via excretion. Steroid sulfates are found in high concentrations in human plasma1 (Table 1); they can serve as intermediates in steroid metabolism2–4 and as precursor pools of biologically active androgens5 and estrogens.6 Glucocorticoid sulfates have been implicated in certain types of hypertension and in the induction of hepatic tyrosine transaminase.
Hydroxylated C18 and C19 Steroids; Their Significance and Factors Related to Their Biosynthesis
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
With free steroid as substrate, uptake into the slice was rapid and tissue content remained fairly constant between 15 min and 2 hr. Steroid sulfates were taken up more slowly, but at incubation times of approximately 2 hr, an average of 18% of both free and sulfurylated estrogen labels became associated with the slice.
Lead optimization of 4-(thio)-chromenone 6-O-sulfamate analogs using QSAR, molecular docking and DFT – a combined approach as steroidal sulfatase inhibitors
Published in Journal of Receptors and Signal Transduction, 2021
The role of estrogens in breast cancer involves two different mechanisms i) Estrogens synthesized in the ovaries and a Luteinizing Hormone Releasing Hormone (LHRH) agonist suppresses the function of pituitary hormone to promote estrogen synthesis in pre-menopausal women, ii) In post-menopausal women, androgen secreted from adrenal glands synthesize estrogens [9,10]. In recent years, studies have been carried out to predict the mechanism by which estrogens are biosynthesized; intensive research is being done in identifying a novel target that prevents the synthesis of estrogens. In mammary gland an enzyme Steroidal Sulfatase (STS) plays a major role in the biosynthesis of estrogen. STS catalyzes the conversion of biologically inactive steroid sulfates (steroid-3-sulfate) into biologically active unsulfated derivatives (3-hydroxy steroid). The three major advantage of targeting STS are i) at molecular level, 87% of breast cancer patients showed higher expression of STS mRNA levels in malignant tissues [11] ii) the activity of STS in cancer tissue is several hundred times more than that of aromatase pathway [12] iii) 5-androstenediol, a steroid circulates in postmenopausal women binds to ER and stimulates the growth of ER + breast cancer cells. Thus, STS would be a more promising target in discovering novel candidate for the treatment of breast cancer.
In vitro studies with two human organic anion transporters: OAT2 and OAT7
Published in Xenobiotica, 2018
Sumathy Mathialagan, Chester Costales, Laurie Tylaska, Emi Kimoto, Anna Vildhede, Jillian Johnson, Nathaniel Johnson, Takami Sarashina, Kenta Hashizume, Caleb D. Isringhausen, Lydia M. M. Vermeer, Andrea R. Wolff, A. David Rodrigues
Identification of a suitable OAT7-selective substrate for use with PHH was unsuccessful, because appreciable uptake was observed with E3S and DHEAS only (Table 1). Both steroid sulfates are known to serve as substrates of OATPs in human primary hepatocytes (Hirano et al., 2004; Kunze et al., 2014; Watanabe et al., 2015; Williamson et al., 2013), consistent with the 84% inhibition by RIFsv (20 µM) in our PHH preparation (Table 3). The fact that OAT7 presented a robust uptake ratio at a low E3S concentration (Table 1 and Supplement Table 2), but uptake in the presence of PHH is dominated by an OATP (OATP1B1), likely reflects the greater hepatic abundance of the latter and its lower Km (∼0.4 versus 9 μM) for the substrate (Huang et al., 2013; Jouan et al., 2016; Shin et al., 2007).
Steroid sulfatase inhibitors: the current landscape
Published in Expert Opinion on Therapeutic Patents, 2021
Hanan S. Anbar, Zahraa Isa, Jana J. Elounais, Mariam A. Jameel, Joudi H. Zib, Aya M. Samer, Aya F. Jawad, Mohammed I. El-Gamal
STS gene is located on the X chromosome (Xp22.31) which it reaches 146 kb, includes 10 exons, and encodes a protein of 583 amino acids [25]. Furthermore, STS is the only enzyme that act on the hydrolysis of steroid sulfates. The sulfates that are hydrolyzed to their unconjugated forms are E1S, dehydroepiandrosterone sulfate (DHEAS), cholesterol sulfate, and pregnenolone sulfate (unconjugated forms: estrone, dehydroepiandrosterone (DHEA), cholesterol, and pregnenolone, respectively)[26].