Sulfation of environmental estrogen-like chemicals by human cytosolic sulfotransferases

硫酸盐偶联是体内外源或内源性化合物（如类固醇和甲状腺激素、儿茶酚胺和胆汁酸）生物转化和/或排泄的主要途径。负责的酶，所谓的“胞质磺酸转移酶”，催化从活性硫酸盐3'-磷酸腺苷5'-磷酸硫酸酯（PAPS）转移磺酸基到含有羟基或氨基的底物化合物。一般认为，磺化可以增加外源性或内源性化合物的水溶性，并促进其从体内清除。本项目为研究硫酸酸化这一体内主要的II期解毒途径是否可以作为环境雌激素失活或处理的手段，制备了重组人胞质硫转移酶，并以双酚a、己烯雌酚、4-辛基酚、4-壬基酚和17 α-乙炔雌醇为底物，对酶活性进行了测试。在检测的7种重组酶中，只有SULT1C亚砜转移酶#1对环境雌激素没有活性。在其他6种硫转移酶中，单酚(P)型苯酚硫转移酶和雌激素硫转移酶对环境雌激素的活性明显高于其他4种硫转移酶。代谢标记实验揭示了环境雌激素在HepG2人肝癌细胞中的硫酸化作用及其硫酸化衍生物的释放。此外，硫酸环境雌激素似乎不能穿透HepG2细胞膜。本课题研究结果清楚地显示了环境雌激素磺化的发生。硫酸酸化的环境雌激素未能穿透HepG2细胞膜，这可能意味着硫酸酸化是去除这些有害化合物的有效机制。为了充分了解不同的硫转移酶在体内环境雌激素失活/去除中的作用，需要进行更多的研究。少

Sulfate conjugation represents a major pathway in vivo for the biotransformation and/or excretion of xenobiotics or endogenous compounds such as steroid and thyroid hormones, catecholamines, and bile acids. The responsible enzymes, so-called "cytosolic sulfotransferases," catalyze the transfer of a sulfonate group from the active sulfate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), to a substrate compound containing either a hydroxyl or an amino group. It is generally believed that sulfation may increase the water-solubility of xenobiotic or endogenous compounds and facilitate their removal from the body.In this project, to investigate whether sulfation, a major Phase II detoxification pathway in vivo, can be employed as a means for the inactivation/disposal of environmental estrogens, recombinant human cytosolic sulfotransferases were prepared and tested for enzymatic activities with bisphenol A, diethylstilbestrol, 4-octylphenol, 4-nonylphenol, and 17 α-ethynylestradiol as substrat … More es. Of the seven recombinant enzymes examined, only SULT1C sulfotransferase #1 showed no activities toward the environmental estrogens tested. Among the other six sulfotransferases, the simple phenol (P)-form phenol sulfotransferase and estrogen sulfotransferase appeared to be considerably more active toward environmental estrogens than the other four sulfotransferases. Metabolic labeling experiments revealed the sulfation of environmental estrogens and the release of their sulfated derivatives by HepG2 human hepatoma cells. Moreover, sulfated environmental estrogens appeared to be incapable of penetrating through the HepG2 cell membrane. The results obtained in this project study showed clearly the occurrence of the sulfation of environmental estrogens. That the sulfated environmental estrogens failed to penetrate through the HepG2 cell membrane may imply sulfation as a useful mechanism for the removal of these hazardous compounds. More studies are warranted in order to fully appreciate the involvement of different sulfotransferases in the inactivation/removal of environmental estrogens in vivo. Less