Kaempferol modulates TCDD- and t-BHQ-induced drug-metabolizing enzymes and luteolin enhances this effect†
The expression of drug-metabolizing enzymes is deeply involved in chemical-induced cancer progression and prevention. The aryl hydrocarbon receptor (AhR) induces phase I, and certain phase II drug-metabolizing enzymes after the binding of ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We have previously demonstrated that luteolin inhibited TCDD-induced AhR transformation, and modulated the expression of drug-metabolizing enzymes through not only the AhR, but also the nuclear factor-erythroid-2-related factor 2 (Nrf2). We have examined the effect of kaempferol on the expression of drug-metabolizing enzymes through modulation of the AhR- and Nrf2-pathways, and the effect of co-treatment with kaempferol and luteolin. Kaempferol dose-dependently inhibited not only the TCDD-induced expression of phase I and phase II drug-metabolizing enzymes, but also the tertiary butylhydroquinone (t-BHQ)-induced expression of phase II drug-metabolizing enzymes, by modulating the AhR- and Nrf2-pathways. Co-treatment with kaempferol and luteolin enhanced the inhibitory effect on the expression of drug-metabolizing enzymes, compared with either kaempferol or luteolin alone. Moreover, co-treatment with kaempferol and luteolin increased the cellular levels of kaempferol without affecting the levels of luteolin. An in vivo study was also performed and the results demonstrated that co-treatment with kaempferol and luteolin enhanced the inhibition of benzo[a]pyrene-induced drug-metabolizing enzymes compared with either kaempferol or luteolin alone, in the liver of ICR mice. These results suggest that luteolin promoted the incorporation of kaempferol into hepatocytes and enhanced the inhibitory effect of kaempferol on chemical-induced drug-metabolizing enzymes. Thus, luteolin enhances the kaempferol-inhibited expression of drug-metabolizing enzymes.