Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases

胞液磺基转移酶(Sults)通常被认为参与了外来化合物的II相解毒和内源化合物的动态平衡。硫磺在体内的硫酸盐化过程中起着重要作用，因此在人和鱼等多种动物中都存在硫磺。最近有报道称，哺乳动物硫磺在自然界中环境雌激素的代谢中起作用。事实上，据报道，人类硫磺催化生成硫酸盐环境雌激素。此外，鱼类直接暴露于环境雌激素，但有关鱼类磺基转移的信息很少。在本工作中，斑马鱼胞液硫磺对几种具有代表性的环境雌激素，如双酚A和包括雌激素在内的类黄酮进行了硫酸盐化。结果表明，该酶对雌酮(E_1)和17-β-雌二醇(E_2)活性较高，命名为SULT1ST#2。该酶对…也表现出较高的活性类黄酮类和烷基酚类化合物较多。此外，几种环境雌激素在调节雌激素浓度的过程中表现出浓度依赖的抑制作用。此外，还研究了大豆异黄酮对人体硫磺的影响。因此，我们研究了几种硫磺编码的单核苷酸多态(CSNPs)对其酶活性的影响以及对雌激素硫化的抑制作用。通过定点突变产生了一些源于cSNPs的氨基酸突变体，并对其进行了表达和纯化。在这些结果中，hSUL1A1变异体^*4(A146T、E181G和R213H)和hSUL1A1变异体^*2(D22Y)的17β-雌二醇的比活力明显低于野生型酶。此外，在hSULT1E1野生型和变异型^*4(P253H)中，绿黄素对E_2硫化的抑制作用也存在差异。综上所述，这些结果表明环境雌激素具有通过抑制雌激素硫化来干扰内分泌介导的事件的能力。在人类中，胞浆硫磺的功能可能受到多种因素的影响，如环境雌激素和cSNPs。较少

Cytosolic sulfotransferases (SULTs) are generally thought to be involved in the phase II detoxification of xenobiotic compounds as well as homeostasis of endogenous compounds. The SULTs play important role in sulfation in vivo, therefore the SULTs are presented in variety animals such as human and fish. Recently, it is reported that mammalian SULTs play a role in metabolism of environmental estrogens in nature. In fact, it is reported that human SULTs catalyze to sulfate environmental estrogens. Otherwise, fishes are directly exposed to environmental estrogens, however, there has been little information about fish sulfotransferases.In this work, it was demonstrated that several representative environmental estrogens such as bisphenol A and flavonoids including estrogen were sulfated by zebrafish cytosolic SULTs. Results showed that the enzyme, designated SULT1 ST #2, displayed high activities toward estrone (E_1) and 17β-estradiol (E_2). This enzyme also displayed high activities towar … More d flavonoids and alkyl phenolic compounds. In addition, several environmental estrogens showed a concentration-dependent inhibition on sulfation to regulate estrogen concentration.Moreover, it was investigated that human SULTs were influenced by soybeans isoflavone. Final, it is clear that human SULTs were inhibited by various environmental estrogens, therefore, it was investigated the effects of coding single nucleotide polymorphisms (cSNPs) of several SULTs on their enzyme activities and on inhibitory effect on estrogen sulfation. A number of SULT amino acid variants deriving from cSNPs were generated by site-directed mutagenesis, expressed, and purified. In these result, specific activities for 17β-estradiol of hSUL1A1 variant ^*4(A146T, E181G and R213H) and hSUL1E1 variant ^*2(D22Y) were markedly decreased as compared with wild-type enzyme. In addition, there were differences in inhibitory effects of glycitein on E_2 sulfation in the hSULT1E1 wild-type and variant^*4 (P253H).In summary, these results suggested that environmental estrogens have a capacity of disrupt endocrine-mediated events by inhibiting estrogen sulfation. In human, it is suggested that the functional roles of cytosolic SULTs may be influenced by various factors such as environmental estrogens and cSNPs. Less