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Impact of Human SULT1E1 Polymorphisms on the Sulfation of 17β-Estradiol, 4-Hydroxytamoxifen, and Diethylstilbestrol by SULT1E1 Allozymes

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Abstract

Background and Objectives

Previous studies have revealed that sulfation, as mediated by the estrogen-sulfating cytosolic sulfotransferase (SULT) SULT1E1, is involved in the metabolism of 17β-estradiol (E2), 4-hydroxytamoxifen (4OH-tamoxifen), and diethylstilbestrol in humans. It is an interesting question whether the genetic polymorphisms of SULT1E1, the gene that encodes the SULT1E1 enzyme, may impact on the metabolism of E2 and these two drug compounds through sulfation.

Methods

In this study, five missense coding single nucleotide polymorphisms of the SULT1E1 gene were selected to investigate the sulfating activity of the coded SULT1E1 allozymes toward E2, 4OH-tamoxifen, and diethylstilbestrol. Corresponding cDNAs were generated by site-directed mutagenesis, and recombinant SULT1E1 allozymes were bacterially expressed, affinity-purified, and characterized using enzymatic assays.

Results

Purified SULT1E1 allozymes were shown to display differential sulfating activities toward E2, 4OH-tamoxifen, and diethylstilbestrol. Kinetic analysis revealed further distinct Km (reflecting substrate affinity) and Vmax (reflecting catalytic activity) values of the five SULT1E1 allozymes with E2, 4OH-tamoxifen, and diethylstilbestrol as substrates.

Conclusions

Taken together, these findings highlighted the significant differences in E2-, as well as the drug-sulfating activities of SULT1E1 allozymes, which may have implications in the differential metabolism of E2, 4OH-tamoxifen, and diethylstilbestrol in individuals with different SULT1E1 genotypes.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA

    Amal A. El Daibani, Fatemah A. Alherz, Maryam S. Abunnaja, Ahsan F. Bairam, Mohammed I. Rasool, Katsuhisa Kurogi & Ming-Cheh Liu

  2. Department of Pharmacology, College of Pharmacy, University of Kufa, Najaf, Iraq

    Ahsan F. Bairam

  3. Department of Pharmacology, College of Pharmacy, University of Karbala, Karbala, Iraq

    Mohammed I. Rasool

  4. Biochemistry and Applied Biosciences, University of Miyazaki, Miyazaki, 889-2192, Japan

    Katsuhisa Kurogi

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This work was supported in part by a grant from National Institutes of Health (Grant # R03HD071146).

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The authors (A.E., F. A., M.A., A.B., M.R., K.K., and M.L.) declare no conflicts of interest.

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AE, FA, MA, AB, and MR performed experiments (cDNA cloning, recombinant protein expression/purification, and enzymatic characterization) and analyzed data. AE, KK, and ML analyzed data and wrote the manuscript. ML devised the project.

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El Daibani, A.A., Alherz, F.A., Abunnaja, M.S. et al. Impact of Human SULT1E1 Polymorphisms on the Sulfation of 17β-Estradiol, 4-Hydroxytamoxifen, and Diethylstilbestrol by SULT1E1 Allozymes. Eur J Drug Metab Pharmacokinet 46, 105–118 (2021). https://doi.org/10.1007/s13318-020-00653-1

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