Discovery of flavonoids as potent inhibitors of CYP1A to alleviate cellular inflammation and oxidative stress induced by benzo[a]pyrene-induced high CYP1A expression.

The environmental pollutant benzo[a]pyrene (BaP) can induce cytochrome P450 family 1 subfamily A (CYP1A) or generate metabolic products that disrupt the balance of oxidative stress, triggering inflammatory responses in the lungs and leading to tissue damage. Flavonoids, known for their natural anti-inflammatory and antioxidant properties, are potential targets for intervention. This study used phenacetin, a specific substrate probe for CYP1A, to evaluate the inhibitory effects of 40 flavonoids on CYP1A. Structure-activity relationship analysis revealed that introducing hydroxyl groups at positions 3- and 6-enhances CYP1A inhibition. Notably, 3,6-dihydroxyflavone (DHF) emerged as a significant inhibitor of CYP1A. In vitro experiments confirmed that DHF effectively inhibits BaP-induced cytochrome P450 family 1 subfamily A member 1 (CYP1A1) in airway epithelial cells and shows dose-dependent inhibition of intracellular and mitochondrial reactive oxygen species (ROS) production. In summary, DHF is a promising CYP1A inhibitor and a potential anti-inflammatory candidate for preventing and treating CYP1A-mediated lung diseases.