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

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

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 rangeof cytotoxic compounds out of the cells. Previously, we demonstrated that the phytoestrogen genistein (GNT) modulatesP-gp expression in hepatocellular carcinoma in vitro. Although several benefcial efects (e.g., antioxidant, antimutagenic,anticancer) have been attributed to GNT, the molecular mechanisms have not been totally elucidated. In the present work,we evaluated the efect of GNT on P-gp expression in rat liver, kidney and ileum. We found that GNT (5 mg/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 remained unchanged after GNT treatment. Hepatic P-gp activity measured with rhodamine-123 and digoxin, bothwell-known P-gp substrates, was also increased. In vitro experiments using hepatocyte primary cell culture demonstratedthat inhibition of ER-α with ICI182/780 did not prevent Mdr1a mRNA up-regulation by GNT (10 µM). In contrast, Mdr1ainduction was suppressed after pregnane X receptor (PXR) inhibition by sulforaphane and knockdown of this nuclear receptor. These fndings were confrmed in vivo by using the PXR antagonist ketoconazole. In conclusion, we demonstrated theinduction of hepatic P-gp expression and activity by GNT in vivo, with PXR being a likely mediator. This suggests that GNT,at concentrations observed in plasma of individuals consuming the phytoestrogen in the diet or through supplements, couldafect the clearance of relevant P-gp substrates of therapeutic use as well as toxicity of environmental and food toxicants.