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Title: Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo

The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen. - Highlights: • Dioscin raised MTX concentration by inhibiting MDR1 in Caco-2 cells. • Dioscin suppresses MDR1 by inhibiting NF-κB signaling pathway in Caco-2 cells. • Dioscin can enhance MTX absorption via inhibiting MDR1 in vivo and in vitro. • Dioscin did not increase MTX-induced gastrointestinal mucosal toxicity.
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [2] ;
  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China)
  2. (China)
Publication Date:
OSTI Identifier:
22439725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 277; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; BROMIDES; CARCINOMAS; DOXORUBICIN; EOSIN; HEMATOXYLIN; IN VITRO; IN VIVO; KETONES; LARGE INTESTINE; MESSENGER-RNA; METHOTREXATE; MONITORING; PERMEABILITY; PHOSPHORYLATION; PROTEINS; RADIOPROTECTIVE SUBSTANCES; RATS; TOXICITY