Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

摘要: IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that structurally similar to laquinimod (LAQ). Both compounds are converted the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ not reported any significant toxic outcomes C2 has shown low toxicity rats; however, their functional resemblance highly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize hepatic transcriptomic changes induced by acute (single-dose) subacute exposure (repeated dosing 5 days followed 5-day recovery period) Sprague-Dawley rats. Exposure leads activation of AHR, altered transcription Cyp1a1. We identify heightened response early after drops off day 10. Acute genes involved antiviral antibacterial responses, which highlights immunomodulator effects this agonist. Subacute causes an oxidative stress liver, consequences require further study target tissues such CNS immune system, both may be compromised patient population.