Transcriptomic impact of IMA-08401, a novel AHR-agonist resembling laquinimod, on rat liver

IMA-08401 (C2) represents a novel AHR agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Although both compounds produce an identical AHR-active metabolite, IMA-06201 (DELAQ) in vivo, C2 generates it to a far greater degree. SAHRMs have been proposed as therapeutic options for autoimmune disorders, including multiple sclerosis. So far, clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, more research is required due to the functional resemblance of these compounds to the highly toxic AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report transcriptomic profiling of rat liver following acute (single-dose) and sub-acute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to high doses of C2. Exposure to C2 leads to activation of the AHR, as shown by changes in mRNA abundance of the prototypical AHR-response gene Cyp1a1. We identify a heightened response early after exposure (1 day) that drops off considerably by day 10. Acute exposure to C2 produces a significant immune response, with a focus on antiviral and antibacterial responses that highlights the dual effects of AhR agonists as immunomodulators. Sub-acute exposure leads to an increase in oxidative stress in the liver, the consequences of which require further study on sensitive tissues, such as the CNS and immune system which may be compromised in patients with the target autoimmune disorders. Young adult male Sprague-Dawley rats were treated by gavage with with either a single dose of C2 (100 mg/kg dissolved in PEG-400at a total volume of 5 ml/kg) or vehicle control alone (PEG-400; 5ml/kg) on day 0 and euthanized on day 1, or repeated doses of C2 (100 mg/kg/day, as above) or vehicle control (PEG-400, 5ml/kg/day) daily for 5 consecutive days (days 0-4) and euthanized on day 9. Liver tissue was harvested for analysis. RNA was isolated and the transcriptome for each animal assayed on separate microarrays.