FICZ (0.01 nM-1 μM) alone or in combination with 50 nM MNF induces sustained CYP1A1 activity and leads to oxidative stress and activation of apoptosis via a mitochondrial-dependent pathway. In HepG2 cells, FICZ stimulates cell growth at low concentrations but inhibits cell growth at high concentrations. FICZ (10,000-30,000 nM) significantly decreases CEH viability with an estimated LC ₅₀ (95% confidence intervals) of 14,000 nM. FICZ shows concentration-dependent effects on EROD activity in CEH cultures, with the mean EC ₅₀ values at 3, 8, and 24 h of 0.016 nM, 0.80 nM, and 11 nM, respectively. FICZ treatment increases transcript expression of CYP1A1 in a dose-dependent manner in both the parental iPSC line and the CYP1A1 targeted clone. CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. CYP1 enzymes plays a role in regulating biological effects of FICZ.
Nuclear export and degradation of the AHR protein are two additional steps in the AHR-mediated signal transduction pathway.
Exposure to AhR agonists causes AhR-expressing cells to downregulate the receptor through the ubiquitin/proteasome degradation pathway.