Glatt Hansruedi, Meinl Walter
Federal Institute for Risk Assessment (BfR), Department Food Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Department of Nutritional Toxicology (HG & WM) and Department of Molecular Toxicology (WM), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
Essays Biochem. 2024 Dec 4;68(4):523-539. doi: 10.1042/EBC20240030.
Cytosolic sulphotransferase (SULT) enzymes catalyse reactions involved in xenobiotic elimination and hormone regulation. However, SULTs can also generate electrophilic reactive intermediates from certain substrates, including the activation of carcinogens. Here, we review toxicological studies of mouse strains with SULT status altered by genetic modification. Knockout mouse strains have been constructed for the enzymes Sult1a1, 1d1, 1e1, 2b1 and 4a1. In addition, transgenic strains are available for human SULT1A1/2. Among SULT knockout mouse strains, reduced fertility (Sult1e1) and early postnatal death (Sult4a1) were observed. In contrast, Sult1a1 or Sult1d1 knockouts and SULT1A1/2 transgenics were healthy and showed no obvious deficiencies. These strains were used in toxicological studies with 13 chemicals. Manipulation of the SULT system altered dramatically the adverse effects of many compounds; thus, very large differences in levels of DNA adducts formed in the liver or other tissues were seen with some chemicals - up to 99.2% decreases in knockouts and 83-fold increases in SULT1A1/2 transgenics. In many cases, these changes were restricted to the tissues in which the corresponding enzymes are expressed, arguing for local activation. However, with some compounds, the kidney was an important target tissue, due to the active transfer to that organ, via the circulation, of reactive sulphuric acid esters.
胞质磺基转移酶（SULT）催化参与外源性物质消除和激素调节的反应。然而，SULT也可从某些底物生成亲电反应性中间体，包括致癌物的活化。在此，我们综述了通过基因修饰改变SULT状态的小鼠品系的毒理学研究。已构建了Sult1a1、1d1、1e1、2b1和4a1酶的基因敲除小鼠品系。此外，还有人SULT1A1/2的转基因品系。在SULT基因敲除小鼠品系中，观察到生育力降低（Sult1e1）和出生后早期死亡（Sult4a1）。相比之下，Sult1a1或Sult1d1基因敲除小鼠以及SULT1A1/2转基因小鼠健康，未表现出明显缺陷。这些品系被用于13种化学物质的毒理学研究。SULT系统的操控显著改变了许多化合物的不良反应；因此，一些化学物质在肝脏或其他组织中形成的DNA加合物水平存在很大差异——基因敲除小鼠中降低了99.2%，而SULT1A1/2转基因小鼠中增加了83倍。在许多情况下，这些变化仅限于相应酶表达的组织，表明是局部活化。然而，对于一些化合物，肾脏是重要的靶组织，因为活性硫酸酯通过循环被主动转运到该器官。
