Cyanidin-3-O-glucoside and its metabolite protocatechuic acid ameliorate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells by regulating apoptotic and Nrf2/p62 pathways.

The present study investigated the protective effects and mechanism of action of cyanidin-3-O-glucoside (C3G) and its major metabolite protocatechuic acid (PCA) against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells. The results demonstrated that C3G and PCA dose-dependently suppressed PhIP-induced mutation in Salmonella typhimurium TA98, and inhibited PhIP-induced cytotoxicity and apoptosis in HepG2 cells. Western blot analysis indicated that C3G and PCA minimized PhIP-induced cell damage by reversing the abnormal expression of Bax/Bcl-2, Cytochrome c, cleaved Caspase-3, XIAP, Nrf2, HO-1, LC3 and p62 involved in intrinsic apoptotic and Nrf2/p62 pathways. Molecular docking results revealed that C3G and PCA were able to interfere with Nrf2 signaling and apoptotic cascade through binding to Keap1 and Bcl-2. Moreover, the protective effect of C3G was stronger than that of PCA. These findings suggested that dietary consumption of food sources rich in C3G can fight against the health risks of heterocyclic aromatic amines.