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

Toxicol Appl Pharmacol. 2014 Jun 1;277(2):146-54. doi: 10.1016/j.taap.2014.03.013. Epub 2014 Mar 26.

Abstract

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.

Keywords: Absorption; Dioscin; Inhibitor κB-α; Methotrexate; Nuclear factor κ-B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / metabolism*
  • Antimetabolites, Antineoplastic / pharmacology
  • Caco-2 Cells
  • Cell Survival / drug effects
  • Diosgenin / analogs & derivatives*
  • Diosgenin / pharmacology
  • Diosgenin / toxicity
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • Enterocytes / drug effects*
  • Enterocytes / metabolism
  • Enterocytes / pathology
  • Genes, Reporter
  • Humans
  • I-kappa B Proteins / metabolism
  • Intestinal Absorption / drug effects*
  • Intestine, Small / drug effects*
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Male
  • Methotrexate / metabolism*
  • Methotrexate / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transfection

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antimetabolites, Antineoplastic
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, rat
  • RNA, Messenger
  • NF-KappaB Inhibitor alpha
  • dioscin
  • multidrug resistance protein 3
  • Diosgenin
  • Methotrexate