Rottkord Ulrike, Röhl Christopher, Ferse Ines, Schulz Marie-Christin, Rückschloss Uwe, Gekle Michael, Schwerdt Gerald, Humpf Hans-Ulrich
Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 45, 48149, Münster, Germany.
Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
Arch Toxicol. 2017 Mar;91(3):1461-1471. doi: 10.1007/s00204-016-1799-3. Epub 2016 Jul 15.
The enigma why the mycotoxin ochratoxin A (OTA) impairs cell and organ function is still not solved. However, an interaction with target molecules is a prerequisite for any observed adverse effect. This interaction depends on characteristics of the target molecule as well as on the OTA molecule itself. OTA has different structural moieties which may be relevant for these interrelations including a halogen (chlorine) and an amino acid group (phenylalanine). To test their importance for the impact of OTA, detailed structure-activity studies with various OTA derivatives were performed. For this, 23 OTA derivatives were available, which were modified by either an exchange of the halogen moiety against another halogen (fluorine, iodine or bromine) or by the amino acid moiety against another one (tyrosine or alanine) or a combination of both. Additionally, the configuration of the 3R carbon atom was changed to 3S. These derivatives were tested in human renal cells for their ability to induce cell death (cytotoxicity, apoptosis, necrosis), their impact on collagen protein secretion and for their influence on gene expression. It turned out that the substitution of the amino acid moiety against tyrosine or alanine almost completely prevented the adverse effects of OTA. The exchange of the halogen moiety had minor effects and the inversion of the stereochemistry at C3 did not prevent the effects of OTA. Therefore, we conclude that the amino acid moiety of OTA is indispensable for the interaction of OTA with its target molecules.
霉菌毒素赭曲霉毒素A（OTA）为何会损害细胞和器官功能这一谜团仍未解开。然而，与靶分子的相互作用是任何观察到的不良反应的先决条件。这种相互作用取决于靶分子的特性以及OTA分子本身。OTA具有不同的结构部分，这些部分可能与这些相互关系有关，包括一个卤素（氯）和一个氨基酸基团（苯丙氨酸）。为了测试它们对OTA影响的重要性，我们对各种OTA衍生物进行了详细的构效关系研究。为此，我们获得了23种OTA衍生物，它们通过将卤素部分换成另一种卤素（氟、碘或溴），或者将氨基酸部分换成另一种氨基酸（酪氨酸或丙氨酸），或者两者结合进行修饰。此外，3R碳原子的构型被改为3S。这些衍生物在人肾细胞中测试了它们诱导细胞死亡（细胞毒性、凋亡、坏死）的能力、对胶原蛋白分泌的影响以及对基因表达的影响。结果表明，将氨基酸部分换成酪氨酸或丙氨酸几乎完全消除了OTA的不良反应。卤素部分的交换影响较小，C3处立体化学的反转并没有阻止OTA的作用。因此，我们得出结论，OTA的氨基酸部分对于OTA与其靶分子的相互作用是不可或缺的。
