Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)

Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)

Bibliographic Details
Main Author: El Daibani, Amal A. Hassan
Language:English
Published: University of Toledo / OhioLINK 2018
Subjects:
Pharmacology
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=toledo1534760747832809
id ndltd-OhioLink-oai-etd.ohiolink.edu-toledo1534760747832809
record_format oai_dc
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-toledo15347607478328092021-08-03T07:08:18Z Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1) El Daibani, Amal A. Hassan Pharmacology Cytosolic sulfotransferases (SULTs), one of the major group of phase II conjugating enzymes in humans, mediate the sulfoconjugation of numerous key endogenous compounds and xenobiotics. SULT1E1, also known as the estrogen sulfotransferase, catalyzes the transfer of the sulfonate moiety (SO3-) of the active donor compound, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to the phenolic acceptor group of steroidal estrogens including endogenous estrogens (17-ß estradiol, estrone and estriol) as well as structurally related xenobiotics. Genetic polymorphisms of SULT1E1 have been reported to correlate with the increase in the risk for breast, ovarian, prostate, and endometrial cancers. The current study was designed to evaluate the impact of the genetic polymorphisms of the SULT1E1 gene on the sulfating activities of coded SULT1E1 allozymes toward endogenous estrogens and structurally related xenobiotics. Following a systematic analysis of SULT1E1 genotypes, five non-synonymous (missense) coding SNPs (cSNPs) of SULT1E1 were selected. Corresponding cDNAs were generated by site-directed mutagenesis and recombinant SULT1E1 allozymes were bacterially expressed and purified by affinity chromatography. By performing sulfotransferase assays, the sulfating activities of the recombinant SULT1E1 allozymes were analyzed with endogenous substrates (17-ß estradiol, estrone, and estriol), xenobiotics (17a-ethinylestradiol, 4-hydroxytamoxifen, and diethylstilbestrol), and a known inhibitor for SULT1E, triclosan.Results obtained indicated that the five SULT1E1 allozymes (SULT1E1-A43D, SULT1E1-A131P, SULT1E1-R186L, SULT1E1-P214T, and SULT1E1-D220V) exhibited differential sulfating activities toward each of the seven substrate compounds. Moreover, SULT1E1 allozymes displayed lower 17-ß estradiol-sulfating activities in the presence of triclosan compared to the wild-type SULT1E1. Further, kinetic analysis revealed the distinct substrate affinity (Km) and catalytic efficiency (Vmax) of different SULT1E1 allozymes toward 17-ß estradiol, 4-hydroxytamoxifen and diethylstilbestrol. In addition, pH-dependence studies on the sulfation of 17-ß estradiol indicated that the optimal pH for the sulfating activity of the wild-type SULT1E1, SULT1E1-A43D, and SULT1E1-A131P was 8.5, while for SULT1E1-R186L, SULT1E1-P214T, and SULT1E1-D220V it was 8. Taken together, these findings clearly indicated the influence of genetic polymorphisms on the sulfating activities of coded SULT1E1 allozymes, which may affect the differential metabolism of endogenous estrogens as well as xenobiotics in individuals with different SULT1E1 genotypes. Additionally, this study provided further evidence that triclosan may differentially act as a substrate and inhibitor for human SULT1E1 allozymes, which may interfere with the hemostasis of endogenous estrogens such as 17-ß estradiol in individuals with different SULT1E1 genotypes. 2018 English text University of Toledo / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=toledo1534760747832809 http://rave.ohiolink.edu/etdc/view?acc_num=toledo1534760747832809 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Pharmacology
spellingShingle Pharmacology
El Daibani, Amal A. Hassan
Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
author El Daibani, Amal A. Hassan
author_facet El Daibani, Amal A. Hassan
author_sort El Daibani, Amal A. Hassan
title Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
title_short Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
title_full Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
title_fullStr Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
title_full_unstemmed Studies on the Functional Relevance of Genetic Polymorphisms of the Human Cytosolic Sulfotransferase 1E1 (SULT1E1)
title_sort studies on the functional relevance of genetic polymorphisms of the human cytosolic sulfotransferase 1e1 (sult1e1)
publisher University of Toledo / OhioLINK
publishDate 2018
url http://rave.ohiolink.edu/etdc/view?acc_num=toledo1534760747832809
work_keys_str_mv AT eldaibaniamalahassan studiesonthefunctionalrelevanceofgeneticpolymorphismsofthehumancytosolicsulfotransferase1e1sult1e1
_version_ 1719454572958711808

Similar Items