In vivo down-regulation of intestinal drug transporters P-glycoprotein and breast cancer resistant protein by Eruca vesicaria leaves extracts

CARBALLO MA; ROMA, MARTÍN IGNACIO; PERONI RN; SALAZAR-SANABRIA AN

Congreso; XII Congreso ALAMCTA VIRTUAL 2021; 2021

ASOCIACIÓN LATINOAMERICANA DE MUTAGÉNESIS, CARCINOGÉNESIS Y TERATOGÉNESIS AMBIENTAL

Phytochemicals present in raw leaves of Eruca vesicaria (rocket salad, arugula) shown to have complex interactions with ABC transporters. The aim of this study is to investigate the effect of chronic Eruca vesicaria extracts on the expression and transport activity of intestinal efflux pumps P-glycoprotein (P-gp), multidrug resistance-associated protein (Mrp2) and breast cancer resistance protein (Bcrp). Male Sprague-Dawley rats were administered 2 g/kg of juice or 100 mg/kg of methanolic extract enriched in phenolic 32 compounds by esophageal gavage 3 times a week for 4 weeks. None of the regimens used generated alterations in body weight, blood pressure, glycemia or lipid profile. Serosal-mucosal transport of the P-gp substrate rhodamine123 was significantly lower and independent of the P-gp inhibitor verapamil in the ileal everted sacs of rats exposed to the juice and methanolic extract of Eruca vesicaria; consistent with the significant decrease in ileal P-gp protein expression. In addition, the exposure to methanolic extract decreased protein expression of Bcrp and the serosal-mucosal transport of its substrate nitrofurantoin in everted sacs from distal jejunum became lower and partially independent of the inhibitor KO143. No differences were observed in the activity nor in Mrp2 expression in rat duodenum. Efflux tests were also performed on differentiated human Caco-2 cells in a range of non-cytotoxic concentrations of juice (350μg-14mg / ml) or methanolic extract (2-2000μg / ml) of Eruca vesicaria. Increased accumulation of R123 was caused by exposure to 1.4-14 mg/ml of juice and 500-1000 μg/ml of methanolic extract, while 2000 μg/ml of methanolic extract increased the accumulation of the BCRP substrate Pheophorbide A. In conclusion, regular intake of Eruca vesicaria extracts down-regulates P-gp, enhancing oral absorption of P-gp substrates. Moreover, extracts of Eruca vesicaria should be studied as possible nutraceutical non-toxic adjuvants to overcome multiresistance in tumor cells overexpressing P-gp and Bcrp.