人类 SULT1E1 多态性对 SULT1E1 同工酶对 17β-雌二醇、4-羟基他莫昔芬和己烯雌酚硫酸化的影响。
Impact of Human SULT1E1 Polymorphisms on the Sulfation of 17β-Estradiol, 4-Hydroxytamoxifen, and Diethylstilbestrol by SULT1E1 Allozymes.
机构信息
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.
Department of Pharmacology, College of Pharmacy, University of Kufa, Najaf, Iraq.
出版信息
Eur J Drug Metab Pharmacokinet. 2021 Jan;46(1):105-118. doi: 10.1007/s13318-020-00653-1.
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 K (reflecting substrate affinity) and V (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.
背景和目的
先前的研究表明，雌激素介导的胞质磺基转移酶（SULT）SULT1E1 介导的磺化作用参与了人 17β-雌二醇（E2）、4-羟基他莫昔芬（4OH-他莫昔芬）和己烯雌酚的代谢。有趣的是，SULT1E1 基因（编码 SULT1E1 酶的基因）的遗传多态性是否会通过磺化作用影响 E2 和这两种药物化合物的代谢。
方法
在这项研究中，选择了 SULT1E1 基因的 5 个错义编码单核苷酸多态性，以研究编码 SULT1E1 同工酶对 E2、4OH-他莫昔芬和己烯雌酚的磺化活性。通过定点诱变生成相应的 cDNA，并通过酶促测定法对细菌表达、亲和纯化和表征的重组 SULT1E1 同工酶进行了研究。
结果
显示纯化的 SULT1E1 同工酶对 E2、4OH-他莫昔芬和己烯雌酚表现出不同的磺化活性。动力学分析进一步揭示了 5 种 SULT1E1 同工酶对 E2、4OH-他莫昔芬和己烯雌酚的不同 K（反映底物亲和力）和 V（反映催化活性）值。
结论
总之，这些发现强调了 SULT1E1 同工酶对 E2 以及药物磺化活性的显著差异，这可能对个体中 E2、4OH-他莫昔芬和己烯雌酚的代谢差异产生影响。不同的 SULT1E1 基因型。
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