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首页> 外文期刊>Toxicology and Applied Pharmacology >Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats
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Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

机译：两种新型选择性芳基烃受体调节剂在Sprague-Dawley大鼠中的毒理学特征

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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 (8.75-92.5 mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100 mg/kg/day; and IMA-07101: 75 mg/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. (C) 2017 Elsevier Inc. All rights reserved.
机译：芳香烃受体（AHR）介导二恶英的毒性，但也起着重要的生理作用。选择性AHR调节剂能在不引起二恶英显著毒性的情况下产生这种受体所赋予的一些效应，目前正受到密切关注。两种新的此类化合物是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）。它们分别代表用于治疗自身免疫性疾病和癌症的药物化合物laquinimod和tasquinimod的AHR活性代谢物，作为双乙酰前体药物。在这里，我们在单次给药（8.75-92.5 mg/kg）和以可达到的最高剂量（IMA-08401:100 mg/kg/天；IMA-07101:75 mg/kg/天）重复给药5天后，对Sprague-Dawley大鼠体内的新化合物进行毒理学评估。没有明显的临床毒性迹象，但体重增加略有减缓，并且治疗诱导了最小的肝髓外造血。此外，胸腺的绝对和相对重量均显著降低。Cyp1a1基因在所有受检组织中的表达均显著增加。其他AHR电池基因的肝诱导谱不同于由2,3,7,8-四氯二苯并对二恶英（TCDD）引起的肝诱导谱。血清临床化学变量中唯一显著的改变是甘油三酯减少和3-羟基丁酸酯增加。肝脏和肾脏视黄醇和视黄酰棕榈酸酯的浓度受影响的方式与TCDD报告的方式基本相同。在体外，新化合物在H4IIE细胞中有效激活CYP1A1。总之，这些新化合物似乎是AHR的有效激活剂，但缺乏二恶英的一些主要特征毒性。因此，它们代表了有前途的新型选择性AHR调制器。（C） 2017爱思唯尔公司版权所有。

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