Glatt H, Bartsch I, Christoph S, Coughtrie M W, Falany C N, Hagen M, Landsiedel R, Pabel U, Phillips D H, Seidel A, Yamazoe Y
German Institute of Human Nutrition, Department of Toxicology, Potsdam-Rehbrücke.
Chem Biol Interact. 1998 Feb 20;109(1-3):195-219. doi: 10.1016/s0009-2797(97)00133-6.
Sulfation is a common final step in the biotransformation of xenobiotics and is traditionally associated with inactivation. However, the sulfate group is electron-withdrawing and may be cleaved off heterolytically in some molecules leading to electrophilic cations which may form adducts with DNA and other important cellular structures. Since endogenous sulfotransferases do not appear to be expressed in indicator cells of standard mutagenicity tests, rat and human sulfotransferases have been stably expressed in his- Salmonella typhimurium strain TA1538 and Chinese hamster V79 cells. Using these recombinant indicator cells, sulfotransferase-dependent genotoxic activities were detected with N-hydroxy-2-acetylaminofluorene, 2-acetylaminofluorene (in the presence of co-expressed rat cytochrome P450 1A2), hycanthone, 1'-hydroxysafrole, alpha-hydroxytamoxifen and various benzylic alcohols derived from polycyclic aromatic hydrocarbons. In several cases, it was critical that the reactive sulfuric acid conjugates were formed directly within the indicator cells, owing to the inefficient penetration of cell membranes. In other cases, spontaneous benzylic substitution reactions with medium components, such as halogenide ions or amino acids, led to secondary, membrane-penetrating reactive species. Different sulfotransferases, including related forms from rat and human, substantially differed in their substrate specificity towards the investigated promutagens. It is known that some sulfotransferases are expressed with high tissue and cell type specificities. This site-dependent expression together with the limitations in the distribution of reactive sulfuric acid conjugates may explain organotropic effects of compounds activated by this metabolic pathway.
硫酸化是外源性物质生物转化中常见的最后一步，传统上与失活相关。然而，硫酸基团具有吸电子性，在某些分子中可能会异裂裂解，产生亲电阳离子，这些阳离子可能与DNA和其他重要的细胞结构形成加合物。由于内源性磺基转移酶似乎不在标准致突变性试验的指示细胞中表达，大鼠和人类磺基转移酶已在鼠伤寒沙门氏菌TA1538组氨酸缺陷型菌株和中国仓鼠V79细胞中稳定表达。使用这些重组指示细胞，检测到N-羟基-2-乙酰氨基芴、2-乙酰氨基芴（在共表达大鼠细胞色素P450 1A2的情况下）、海恩酮、1'-羟基黄樟素、α-羟基他莫昔芬以及源自多环芳烃的各种苄醇具有磺基转移酶依赖性的遗传毒性活性。在几种情况下，由于细胞膜穿透效率低，至关重要的是反应性硫酸结合物直接在指示细胞内形成。在其他情况下，与介质成分（如卤离子或氨基酸）的自发苄基取代反应会产生二级膜穿透性反应物种。不同的磺基转移酶，包括大鼠和人类的相关形式，对所研究的前诱变剂的底物特异性有很大差异。已知一些磺基转移酶以高组织和细胞类型特异性表达。这种位点依赖性表达以及反应性硫酸结合物分布的局限性可能解释了通过该代谢途径活化的化合物的器官otropic效应。
