PT  - JOURNAL ARTICLE
AU  - Ishiwara, Mitsuteru
AU  - Aoki, Yasuo
AU  - Takagaki, Hidetsugu
AU  - Ui, Michio
AU  - Okajima, Fumikazu
TI  - TA-270 [4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1<em>H</em>)-quinolinone], an Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced by IgE Receptor Stimulation in RBL-2H3 Cells
AID  - 10.1124/jpet.103.055145
DP  - 2003 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 583--588
VI  - 307
IP  - 2
4099  - http://jpet.aspetjournals.org/content/307/2/583.short
4100  - http://jpet.aspetjournals.org/content/307/2/583.full
SO  - J Pharmacol Exp Ther2003 Nov 01; 307
AB  - 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-α, 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. The American Society for Pharmacology and Experimental Therapeutics