[25] Hydroxysteroid sulfotransferase

Lyon, Ellen Sue; Marcus, Carol J.; Wang, Jun-Lan; Jakoby, William B.

doi:10.1016/s0076-6879(81)77027-7

Cited by 21 publications

(18 citation statements)

References 5 publications

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“…Although the reduction of estrone into 17a-estradiol was reported with 3(17)a-HSD of rabbit kidney and liver, 7) there is no report on the enzyme that catalyzes the reduction of DHEA and its sulfate into the 17a-hydroxymetabolites. In addition, the K m values for DHEA of the two isoforms of mouse 3(17)a-HSD are lower by more than one order of magnitude than those of other DHEA-metabolizing enzymes, such as human 17b-HSD type 5, 33) human 17b-HSD type 1, 34) rat alcohol sulfotransferase, 35) and rat and human 7a-hydroxylase. 36) The K m values for DHEA sulfate of mouse 3(17)a-HSDs are also lower than that of human steroid sulfatase.…”

Section: )mentioning

confidence: 94%

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Ishikura

Usami

Nakajima

et al. 2004

Biological & Pharmaceutical Bulletin

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Mouse kidney contains two 3(17)a a-hydroxysteroid dehydrogenases (HSDs) that show essentially the same properties except for their isoelectric points. However, the structural differences and physiological roles of the two enzymes remain unknown. In this study, we have isolated cDNAs for the two 3(17)a a-HSDs from a total RNA sample of mouse kidney by reverse transcription-PCR. The identity of the cDNAs was confirmed by characterization of the recombinant enzymes that showed the same molecular weights, pI values, pH optima, substrate specificity and inhibitor sensitivity as those of the enzymes from mouse kidney. We also found that the recombinant enzymes reduce precursors of neuroactive progesterone derivatives, 5a a-dihydrotestoserone, deoxycorticosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and estrone at low K m values of 0.3-2 m mM. The two enzymes belonged to the aldo-keto reductase (AKR) family, and their 323-amino acid sequences differed only by five amino acids. The sequences of the two isoforms are identical to those of proteins that are predicted to be encoded in a gene for AKR1C21 in the database of the mouse genome. However, the mRNAs for the two isoforms were expressed in mouse kidney and other tissues, in which their expression levels were different. The results indicate an important role of 3(17)a a-HSD in controlling the concentrations of various steroid hormones in the mouse tissues, and suggest the existence of two genes for the two isoforms of the enzyme.

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Section: )mentioning

confidence: 94%

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Ishikura

Usami

Nakajima

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Tamoxifen metabolites were investigated as substrates for hSULT2A1 using a previously described protocol that determines the incorporation of a radiolabeled sulfuryl moiety from [ 35 S]PAPS into products of the reaction (Lyon et al, 1981). Each 50-ml reaction was performed at pH 7.4 and contained 0.25 M potassium phosphate, 0.20 mM [ 35 S]PAPS, 8.3 mM 2-mercaptoethanol, and the indicated concentrations of tamoxifen metabolite dissolved in dimethylsulfoxide (DMSO), with a final DMSO concentration of 2% (v/v).…”

Section: Methodsmentioning

confidence: 99%

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

2014

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Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an a-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with K i values of 3.5 and 2.8 mM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited K i values of 12.7 and 9.8 mM, respectively, whereas corresponding K i values of 19.4 and 17.2 mM were observed with DHEA as substrate. A K i value of 9.1 mM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 mM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules.

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“…higher than the yield following the affinity-purification step), but this could be due to the fact that it was necessary to employ the dye-binding method [34] of protein determination for these highly purified fractions. The procedure followed differed from that reported by other authors [8,35, 361, but we found that the introduction of a final clean-up step involving FPLC chromatography on MonoQ was necessary in order to remove all contaminating proteins and so produce a preparation of sufficient purity for antibody production. Electrophoresis of the purified protein on an SDS/polyacrylamide gel (Fig.…”

Section: Purification Of Dhea Stmentioning

confidence: 74%

Immunochemical characterisation of a dehydroepiandrosterone sulfotransferase in rats and humans

Sharp

Barker

Coughtrie

et al. 1993

European Journal of Biochemistry

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A member of the rat liver hydroxysteroid sulfotransferase (ST) enzyme family metabolising dehydroepiandrosterone (DHEA) was purified from female rats and used to raise rabbit polyclonal antibodies. Characterisation of this antibody preparation demonstrated that it was specific for DHEA ST, and recognised a single 30-kDa protein on immunoblot analysis of rat liver cytosol which was expressed preferentially in female rat liver, and immunohistochemical localisation of the protein in female rat liver determined that DHEA ST was distributed homogeneously in the cytoplasm of hepatocytes. Examination of the extrahepatic expression of this protein showed it to be located predominantly in the liver, although a small amount of enzyme activity was found in the kidney which was not apparently subject to the same sex difference as the hepatic activity. Immunological analysis suggested that this activity was not due to the action of DHEA ST, but to another, unidentified ST isozyme. The antibody cross-reacted strongly with adult human liver DHEA ST, recognising a protein of 35 kDa on immunoblotting. Using this antibody preparation, the distribution of DHEA ST in mid-trimester human fetal tissues was examined, and it was shown that the enzyme is expressed in the adrenal and liver, but not to any significant extent in the kidney or lung. This antibody therefore provides a powerful tool for investigating the function of DHEA ST.Sulfation is an important pathway of metabolism for a host of xenobiotics (e.g. drugs, carcinogens, environmental chemicals) and endogenous compounds (e.g. steroid hormones, bile acids, neurotransmitters and small peptides j, which in general (though not always) reduces the biological activity of compounds through the attachment of a polar sulfate group to various hydroxyl and amine groups [l, 21. These reactions are catalysed by a family of sulfotransferase isozymes (ST), present in the cytosolic fraction of the liver and other tissues. In rats, a number of subfamilies of ST have been discovered, which exhibit enzyme activities towards different classes of substrate, including phenol ST, hydroxysteroid ST and estrone ST, and it is believed, based on protein-purification experiments and the sex differences in the expression of the different activities, that each of these subfamilies comprises a number of different ST enzymes with distinct but overlapping substrate specificities Abbreviations. DHEA, dehydroepiandrosterone ; DHEA-S, dehydroepiandrosterone sulfate ; ST, sulfotransferase; PAdoPS, 3'-phosphoadenosine 5'-phosphosulfate; FITC, fluorescein isothiocyanate; PAdoP, adenosine 3',5'-diphosphate. Dehydroepiandrosterone (DHEA) is an important steroid hormone, and its sulfate ester (DHEA-S) is the major circulating steroid. The exact physiological role(s) of DHEA (and DHEA-S) still remains unclear, although it has been established that DHEA-S is a good substrate for steroid biosynthesis [18-201, and much speculation has appeared regarding the observed anticancer [21], anti-obesity [22] and antidiabetic [2...

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[25] Hydroxysteroid sulfotransferase

Cited by 21 publications

References 5 publications

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

Immunochemical characterisation of a dehydroepiandrosterone sulfotransferase in rats and humans

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