Phloretamide, an apple phenolic compound, activates the Nrf2/ARE pathway in human hepatocytes.

The aim of this study was to evaluate the effect of phloretamide (PA), an apple constituent, on the activation of the Nrf2 transcription factor and the expression of its target genes: glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) in normal human THLE-2 hepatocytes and the hepatoma HepG2 cell line. PA did not show significant cytotoxicity towards THLE-2 cells but such an effect was observed in HepG2 cells (IC(50) ∼200μM). The treatment of cells with PA resulted in the translocation of Nrf2 from cytosol to nucleus in both cell lines, but increased the level of its transcript and protein only in THLE-2 cells. In this cell line an increased level of GSTA, GSTP, GSTT, NQO1 mRNA was also observed. Increased expression of GSTs was confirmed by enhancement of their protein levels. The increase in p53 protein content observed in THLE-2 may be associated with its stabilization induced by the enhancement of NQO1 level. PA did not affect Nrf2, GSTs, NQO1 or HO-1 expression in HepG2 cells. These results suggest that PA has rather chemopreventive than chemiotherapeutic potential and acts similarly as apple dihydrochalcones through the induction of detoxification/antioxidative enzymes.