CYP1A1 and CYP3A4 modulation by dietary flavonoids in human intestinal Caco-2 cells

Flavonoids have been proposed to exert beneficial effects in a multitude of disease states. However, evidence of potential toxic actions has also emerged. Since large doses of flavonoids can be encountered in the intestine simultaneously with ingested drugs and pollutants, this study aimed at investigating nine individual flavonoid compounds and their interactions with the major intestinal isoforms of cytochrome P450, i.e. CYPs 1A1 and 3A4, using human intestinal Caco-2 cells cultivated in a serum-free medium. Genistein, quercetin and chrysin provoked a dose-dependent inducing effect on the CYP1A1 activity, measured with the EROD assay. However, they did not affect the CYP1A1 mRNA expression, suggesting they are not aryl hydrocarbon receptor-ligands in intestinal cells and act at a post-transcriptional level. Chrysin, at 50 μM, was detected as a potent inhibitor of the TCDD-induced CYP1A1 activity, leading the activity to ca. 10% of the TCDD-control value (n = 3), this effect involving, at least partly, direct interactions at the enzyme level. Quercetin was also shown to significantly inhibit the constitutive CYP3A4 activity, measured by the 6β-(OH)-testosterone assay, and to impair its induction by 1,25-vitamin D3. Chrysin, quercetin and genistein, were detected as significant inhibitors of the 1,25-vitamin D3-induced CYP3A4 activity. In vivo, these effects could result in reduced activation of procarcinogens and/or in drug bioavailability limitation. They underline the importance of intestinal studies to assess food safety and health risks linked to the ingestion of flavonoid-enriched supplements or functional foods.