Mahiout Selma, Lindén Jere, Esteban Javier, Sánchez-Pérez Ismael, Sankari Satu, Pettersson Lars, Håkansson Helen, Pohjanvirta Raimo
Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Finland.
Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, Finland.
Toxicol Appl Pharmacol. 2017 Jul 1;326:54-65. doi: 10.1016/j.taap.2017.04.020. Epub 2017 Apr 20.
The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.
芳基烃受体（AHR）介导二噁英的毒性，但也发挥着重要的生理作用。选择性AHR调节剂目前正受到密切关注，这类调节剂能引发该受体产生的一些效应，却不会导致二噁英那样显著的毒性。两种新型此类化合物分别是IMA - 08401（N - 乙酰基 - N - 苯基 - 4 - 乙酰氧基 - 5 - 氯 - 1,2 - 二氢 - 1 - 甲基 - 2 - 氧代喹啉 - 3 - 甲酰胺）和IMA - 07101（N - 乙酰基 - N -（4 - 三氟甲基苯基）- 4 - 乙酰氧基 - 1,2 - 二氢 - 5 - 甲氧基 - 1 - 甲基 - 2 - 氧代喹啉 - 3 - 甲酰胺）。它们作为二乙酰前药，分别是用于治疗自身免疫性疾病和癌症的药物化合物拉喹莫德和他喹莫德的具有AHR活性的代谢产物。在此，我们在斯普拉格 - 道利大鼠中对这些新型化合物进行了毒理学评估，单次给药剂量为8.75 - 92.5mg/kg，以及在可达到的最高剂量下进行为期5天的重复给药（IMA - 08401：100mg/kg/天；IMA - 07101：75mg/kg/天）。没有明显的毒性临床体征，但体重增加略有迟缓，且这些处理诱导了最小程度的肝脏髓外造血。此外，胸腺的绝对重量和相对重量均显著降低。在所有检测的组织中，Cyp1a1基因表达大幅增加。其他AHR相关基因的肝脏诱导模式与2,3,7,8 - 四氯二苯并 - p - 二噁英（TCDD）所引起的不同。血清临床化学变量中唯一显著的变化是甘油三酯降低和3 - 羟基丁酸增加。肝脏和肾脏中的视黄醇及视黄醇棕榈酸酯浓度受影响的方式与TCDD报道的大致相同。在体外，这些新型化合物在H4IIE细胞中能有效激活CYP1A1。总体而言，这些新型化合物似乎可作为AHR的有效激活剂，但缺乏二噁英的一些主要特征性毒性。因此，它们代表了有前景的新型选择性AHR调节剂。
