| Autor: |
Semeniuk M; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Ceré LI; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Ciriaci N; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Bucci-Muñoz M; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Villanueva SSM; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Mottino AD; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Catania VA; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina., Rigalli JP; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Ruiz ML; Instituto de Fisiología Experimental (CONICET)-Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Suipacha 570, 2000, Rosario, Argentina. ruiz@ifise-conicet.gov.ar. |
| Abstrakt: |
P-glycoprotein (P-gp) is an ABC transporter exhibiting high pharmacotoxicological relevance by extruding a wide range of cytotoxic compounds out of the cells. Previously, we demonstrated that the phytoestrogen genistein (GNT) modulates P-gp expression in hepatocellular carcinoma in vitro. Although several beneficial effects (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 effect 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, both well-known P-gp substrates, was also increased. In vitro experiments using hepatocyte primary cell culture demonstrated that inhibition of ER-α with ICI182/780 did not prevent Mdr1a mRNA up-regulation by GNT (10 µM). In contrast, Mdr1a induction was suppressed after pregnane X receptor (PXR) inhibition by sulforaphane and knockdown of this nuclear receptor. These findings were confirmed in vivo by using the PXR antagonist ketoconazole. In conclusion, we demonstrated the induction 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, could affect the clearance of relevant P-gp substrates of therapeutic use as well as toxicity of environmental and food toxicants. |
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