TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an anti-asthmatic agent, inhibits leukotriene production induced by IgE receptor stimulation in RBL-2H3 cells

J Pharmacol Exp Ther. 2003 Nov;307(2):583-8. doi: 10.1124/jpet.103.055145. Epub 2003 Sep 11.

Abstract

A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-alpha, and production of immunologically detective leukotrienes. These antigen-induced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Asthmatic Agents / pharmacology*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Calcimycin / pharmacology
  • Cells, Cultured
  • Cinnamates / pharmacology*
  • Eosinophils / drug effects
  • Eosinophils / metabolism
  • Humans
  • Ionophores / pharmacology
  • Leukotrienes / metabolism*
  • Lipoxygenase Inhibitors
  • Mast Cells / drug effects*
  • Mast Cells / enzymology
  • Mast Cells / metabolism
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Quinolones / pharmacology*
  • Receptors, IgE / physiology*
  • Tumor Necrosis Factor-alpha / metabolism
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Anti-Asthmatic Agents
  • Cinnamates
  • Ionophores
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Quinolones
  • Receptors, IgE
  • TA 270
  • Tumor Necrosis Factor-alpha
  • Calcimycin
  • Arachidonate 5-Lipoxygenase
  • beta-N-Acetylhexosaminidases