Single and concerted effects of benzo[a]pyrene and flavonoids on the AhR and Nrf2-pathway in the human colon carcinoma cell line Caco-2

As phytochemicals have the potential to counteract adverse effects of carcinogens we investigated the influence of the flavonoids quercetin and kaempferol on benzo[a]pyrene (BaP) mediated effects on human colon cancer cells, Caco-2. We focused on concerted effects on the expression of AhR and Nrf2 pathway components. In contrast to kaempferol, BaP and quercetin efficiently induced CYP1A1, CYP1A2 and CYP1B1-mRNA in Caco-2 cells. BaP not only acted via AhR activation but sustainably also by increasing AhR and by down-regulating AhRR mRNA. The flavonoids did not affect AhR expression but counteracted the BaP mediated AhRR repression. Only quercetin was found to induce AhRR mRNA. ARNT mRNA appeared to be slightly but significantly down-regulated by BaP as well as by flavonoids while expression of AIP was not or only slightly modulated. The Nrf2 pathway was activated by BaP and by the flavonoids shown by induction of Nrf2 and several of its target genes such as NQO1, GSTP1, GSTA1 and GCLC. Induction effects of 10 μm BaP on Nrf2, GSTP1 and NQO1 were abolished by the flavonoids. In summary, we show that quercetin supports AhR mediated effects. Both flavonoids, however, may counteract the effects of BaP on expression of AhR, AhRR, Nrf2, GSTP1 and NQO1. In conclusion, quercetin appears to have two faces, a flavonoid-like one and a PAH-like one which supports Ahr-mediated effects while kaempferol acts “just like a flavonoid”. Thus, flavonoids have to be treated individually with respect to their anti-adverse activity.