Modulation of cytochrome P450 1A1 expression and activity in intestinal Caco-2 cells by components of Ginkgo biloba-based dietary supplements

Ginkgo biloba is largely consumed as food supplement, because it could contribute to memory improvement by acting on cerebrovascular insufficiency. Among the large variety of phytochemicals contained in Ginkgo biloba leaves and extracts, flavonols (mainly kaempferol, quercetin and isorhamnetin) represent the largest part. Several unique terpenoids (ginkgolides A, B, C, J and bilobalide) are also present. In the present study, we investigated the modulation of cytochrome P450 (CYP) 1A1 enzymatic activity and expression in the intestinal Caco-2 cell line by either Ginkgo biloba extracts, by major individual secondary metabolites or by mixtures of these constituents in realistic proportions. Plausible used intestinal concentrations were calculated on the basis of recommended daily intake and quantitative analysis of major constituents in dietary supplements. Preliminary results suggest that (−)-bilobalide, but not the other terpenoids, induces a dose-dependent increase of CYP1A1 activity (measured through 7-ethoxyresorufin O-deethylation, EROD) after 6 h treatment of the Caco-2 cells. RT-PCR highlighted an increase of mRNA after 3 h treatment with (−)-bilobalide, suggesting the involvement of a transcriptional mechanism. Furthermore, a strong dose-dependent inhibition of benzo[a]pyrene (B[a]P)-induced EROD activity was shown after 6 h co-treatment with kaempferol, quercetin or isorhamnetin. This antagonistic effect was conserved with mixtures of the three flavonols and of the eight pre-cited major secondary metabolites. These preliminary results suggest that frequent consumption of Ginkgo biloba-based dietary supplements may influence CYP1A1 expression and activity in intestinal cells, leading to possible toxicological interactions.