Regulation of hepatic P-gp expression and activity by genistein in rats

SEMENIUK, M.; CERÉ, L. I.; CIRIACI, N.; BUCCI-MUÑOZ, M.; VILLANUEVA, S. S. M.; MOTTINO, A. D.; CATANIA, V. A.; RIGALLI, J. P.; RUIZ, MARÍA LAURA

ARCHIVES OF TOXICOLOGY.

SPRINGER

Año: 2020 vol. 94 p. 1625 - 1635

0340-5761

P-glycoprotein (P-gp) is an ABC transporter exhibiting high pharmacotoxicological relevance by extruding a wide range of cytotoxic compounds out ofthe cells. Previously we demonstratedthat the phytoestrogen genistein (GNT) modulates P-gp expression in hepatocellularcarcinoma in vitro. Although several beneficial effects(e.g. antioxidant, antimutagenic, anticancer) have been attributed to GNT, themolecular mechanisms have not been totally elucidated. In the present work, we evaluated the effect ofGNT on P-gp expression in rat liver, kidney and ileum. We found that GNT (5mg/kg daily s.c. 3 days) increased hepatic P-gp expression and also Mdr1a(one of the genes encoding P-gp) mRNA levels. Renal and intestinal P-gp remainedunchanged after GNT treatment. Hepatic P-gp activity measured with rhodamine-123and digoxin, both well-known P-gp substrates, was also increased. In vitroexperiments using hepatocyte primary cell culture demonstrated that inhibitionof ER-α with ICI182/780 did not prevent Mdr1a mRNA up-regulation by GNT(10 µM). In contrast, Mdr1a induction was suppressed after pregnane Xreceptor (PXR) inhibition by sulforaphane and knock down of this nuclearreceptor. These findings were confirmed in vivo by using the PXRantagonist ketoconazole. In conclusion, wedemonstrated the induction of hepatic P-gp expression and activity by GNT invivo, being PXR a likely mediator. This suggests that GNT, atconcentrations observed in plasma of individuals consuming the phytoestrogenwithin the diet or through supplements, could affect the clearance of relevant P-gpsubstrates of therapeutic use as well as toxicity of environmental and food toxicants.