The pregnane X receptor (PXR) has been established to induce chemoresistance and metabolic diseases. Ochratoxin A (OTA), a mycotoxin, decreases the expression of PXR protein in human primary hepatocytes. OTA is chlorinated and has a methylated lactone ring. Both structures are associated with OTA toxicity. The study was to test the hypothesis that structural modifications differentially impact PXR blocking activity over cytotoxicity. To test this hypothesis, OTA-M and OTA-Cl/M were synthesized. OTA-M lacked the methyl group of the lactone-ring, whereas OTA-Cl/M had neither the methyl group nor the chlorine atom. The blocking activity of PXR activation was determined in a stable cell line, harboring both PXR (coding sequence) and its luciferase element reporter. OTA-Cl/M showed the highest blocking activity, followed by OTA-M and OTA. OTA-Cl/M was 60 times as potent as the common PXR blocker ketoconazole based on calculated IC50 values. OTA-Cl/M decreased by 90% the expression of PXR protein and was the least cytotoxic among the tested compounds. Molecular docking identified that OTA and its derivatives interacted with different sets of residues in PXR, providing a molecular basis for selectivity. Excessive activation of PXR has been implicated in chemoresistance and metabolic diseases. Downregulation of PXR protein expression likely delivers an effective mechanism against structurally diverse PXR agonists.

中文翻译：

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黄曲霉毒素 A 的脱氯和脱甲基增强 PXR 活化的阻断活性，抑制 PXR 表达并降低细胞毒性

孕烷 X 受体 (PXR) 已被建立以诱导化学抗性和代谢疾病。Ochratoxin A (OTA) 是一种真菌毒素，可降低人原代肝细胞中 PXR 蛋白的表达。OTA 被氯化并具有甲基化内酯环。这两种结构都与 OTA 毒性有关。该研究旨在检验结构修饰对 PXR 阻断活性的影响超过细胞毒性的假设。为了验证这一假设，合成了 OTA-M 和 OTA-Cl/M。OTA-M 缺少内酯环的甲基，而 OTA-Cl/M 既没有甲基也没有氯原子。PXR 激活的阻断活性是在稳定细胞系中测定的，该细胞系含有 PXR（编码序列）及其荧光素酶元件报告基因。OTA-Cl/M 显示出最高的阻断活性，其次是 OTA-M 和 OTA。根据计算的 IC50 值，OTA-Cl/M 的效力是普通 PXR 阻断剂酮康唑的 60 倍。OTA-Cl/M 使 PXR 蛋白的表达降低了 90%，并且是测试化合物中细胞毒性最小的。分子对接鉴定出 OTA 及其衍生物与 PXR 中不同组的残基相互作用，为选择性提供了分子基础。PXR 的过度激活与化学抗性和代谢疾病有关。PXR 蛋白表达的下调可能提供了一种针对结构多样的 PXR 激动剂的有效机制。分子对接鉴定出 OTA 及其衍生物与 PXR 中不同组的残基相互作用，为选择性提供了分子基础。PXR 的过度激活与化学抗性和代谢疾病有关。PXR 蛋白表达的下调可能提供了一种针对结构多样的 PXR 激动剂的有效机制。分子对接鉴定出 OTA 及其衍生物与 PXR 中不同组的残基相互作用，为选择性提供了分子基础。PXR 的过度激活与化学抗性和代谢疾病有关。PXR 蛋白表达的下调可能提供了一种针对结构多样的 PXR 激动剂的有效机制。