Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Mustialankatu 1, 00790 Helsinki, Finland.
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza, 1, 20126 Milan, Italy.
Toxicol In Vitro. 2018 Oct;52:178-188. doi: 10.1016/j.tiv.2018.06.010. Epub 2018 Jun 13.
The mediator of dioxin toxicity, aryl hydrocarbon receptor (AHR), has also important physiological functions. Selective AHR modulators (SAHRMs) share some effects of dioxins, except for their marked toxicity. We recently characterised toxicologically two novel SAHRMs, prodrugs IMA-08401 and IMA-07101 in rats, demonstrating that they are far less deleterious than the most toxic AHR-agonist, TCDD. Here, we analysed the in vitro toxicity and in silico AHR binding of the respective active, deacetylated metabolites, IMA-06201 (N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-06504 (N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). In H4IIE rat hepatoma cells, IMA-06201 and IMA-06504 induced CYP1A1 with comparable potencies and efficacies to those of TCDD. They had little effect on cell viability as assessed by LDH leakage and MTT reduction assays, and were not mutagenic in the Ames test, but IMA-06504 elicited a maximally 2.7-fold increase in micronuclei. Molecular docking simulations showed that similar to TCDD, they occupy the central region of AHR ligand binding cavity. Hence, while showing low to negligible in vitro toxicity, these novel SAHRMs bind to the AHR qualitatively in a similar fashion to TCDD, and appear comparably powerful AHR agonists. Combined with our earlier results demonstrating that they seem considerably less toxic in vivo than TCDD, these compounds are thus highly interesting new SAHRMs.
二恶英毒性的介体，芳烃受体（AHR），也具有重要的生理功能。选择性 AHR 调节剂（SAHRMs）除了具有明显的毒性外，还具有与二恶英相似的一些作用。我们最近在大鼠中对两种新型 SAHRM 前药 IMA-08401 和 IMA-07101 的毒理学特征进行了描述，证明它们的危害性远低于最毒的 AHR 激动剂 TCDD。在这里，我们分析了相应的活性去乙酰化代谢物 IMA-06201（N-乙基-N-苯基-5-氯-1,2-二氢-4-羟基-1-甲基-2-氧代-3-喹啉羧酸酰胺）和 IMA-06504（N-（4-三氟甲基苯基）-1,2-二氢-4-羟基-5-甲氧基-1-甲基-2-氧代-3-喹啉羧酸酰胺）的体外毒性和计算机模拟 AHR 结合。在 H4IIE 大鼠肝癌细胞中，IMA-06201 和 IMA-06504 以与 TCDD 相当的效力诱导 CYP1A1。它们对细胞活力的影响很小，通过 LDH 漏出和 MTT 减少测定评估，并且在 Ames 试验中没有致突变性，但 IMA-06504 引起微核最大增加 2.7 倍。分子对接模拟表明，它们与 TCDD 相似，占据 AHR 配体结合腔的中央区域。因此，虽然这些新型 SAHRM 显示出低至可忽略不计的体外毒性，但它们以与 TCDD 相似的方式定性地与 AHR 结合，并且似乎是同样强大的 AHR 激动剂。结合我们之前的结果表明，它们在体内似乎比 TCDD 毒性小得多，这些化合物因此是非常有趣的新型 SAHRM。
