Myricetin inhibits CYP3A4, GST, and MRP1 in hepatic cancer cells

Abstract

AbstractHerbal and nutritional supplements are widely used to prevent and treat many diseases, including cancer. Tumor cells modify metabolic enzyme systems like CYP3A4 and GST. They also overexpress MRP1, an ATP-binding cassette transporter subfamily G (ABCG2) member. Drug efflux may increase, reducing tumor cell drug accumulation and developing drug resistance that leads to significant obstacles in cancer care. Natural products' ability to overcome cancer's multidrug resistance is interesting. Their ability to affect several targets makes them valuable in addressing drug resistance from diverse approaches. The potential of natural flavonoid; Myricetin (MYR) to modulate CYP3A4, GST, and MRP1 activity and expression in hepatic cancer cells was evaluated to prove its targeting and preventing these pathways of multidrug resistance. The cell proliferation of MYR was determined using an MTT assay. Specific enzyme assays, efflux assay, and gene expression using RT-PCR were used to evaluate MYR effect in hepatic cell lines HepG-2 and Huh-7. MYR has a noteworthy cytotoxic effect compared to doxorubicin (DOX) with IC50 > 100 μM in HepG-2 and Huh-7 cells. MYR showed potent inhibition of CYP3A4 and GST enzyme activity and MRP1 efflux function and downregulated their gene expression in a dose-dependent manner in both cells. MYR100 dose was the most significant effective dose. MRY100 decreased CYP3A4 activity by 67.5% (P < 0.05) and 55% (P < 0.01) and downregulated the gene by 0.2-fold (P < 0.001) and 0.3-fold (P < 0.001) in HepG-2 and Hub-7 cells, respectively. After treatment with MRY100, GST activity decreased significantly in both cells, reaching 47.6% (P < 0.001) and 33.2% and GST gene downregulation was 0.12 and 0.21-fold (P < 0.001). MRY100 inhibited MRP1 efflux pump 2.3 times (P < 0.001) and 1.9 times (P < 0.001) more effectively than PC, resulting in a 0.23-fold and 0.12-fold downregulation of MRP1 genes in HepG-2 and Hub-7 cells. The result will validate the use of MYR to interact with the metabolism phases and could be used as adjuvant therapy in cancer prevention and treatment approaches.