Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
Laboratory of Toxicology, National Institute for Health and Welfare, FI-70210 Kuopio, Finland.
Int J Mol Sci. 2019 Mar 19;20(6):1370. doi: 10.3390/ijms20061370.
IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of . We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.
IMA-08401（C2）是一种新型芳基烃受体（AHR）激动剂和选择性 AHR 调节剂（SAHRM），其结构与拉喹莫德（LAQ）相似。这两种化合物在体内均转化为 AHR 活性代谢物 DELAQ（IMA-06201）。SAHRM 已被提议作为各种自身免疫性疾病的治疗选择。LAQ 的临床试验未报告任何明显的毒性结果，C2 在大鼠中表现出低毒性；然而，它们与高度毒性的 AHR 激动剂 2,3,7,8-四氯二苯并对二恶英（TCDD）的功能相似，引起了人们的关注。在这里，我们描述了 C2 在 Sprague-Dawley 大鼠中急性（单次剂量）和亚急性（连续 5 天给药后 5 天恢复期）暴露引起的肝转录组变化。C2 的暴露导致 AHR 的激活，如 的转录改变所示。我们发现暴露后早期反应增强，第 10 天下降。C2 的急性暴露导致参与抗病毒和抗菌反应的基因转录发生变化，这突出了这种 AHR 激动剂的免疫调节剂作用。亚急性暴露导致肝脏发生氧化应激反应，需要进一步研究中枢神经系统和免疫系统等靶组织的后果，这两个组织在该患者群体中可能受到影响。
