Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Abstract

Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C₄ from lung fragments of guinea pigs and the effects of E6080 on the release of LTB₄ and LTC₄ from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mML-cysteine significantly increased LTC₄ release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB₄ and LTQ release from passively sensitized human (IC₅₀: LTB₄ 0.08 µM, LTC₄ 0.2 µM) and guinea-pig lung fragments (IC₅₀: LTQ 1.1 µM). The LTB₄ and LTQ releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients’ leukocytes (basophils, antigen) were inhibited by E6080 with IC₅₀ values of below 1.0 µM Furthermore, the LTQ release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC₅₀ of 0.2 µM The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC₅₀ of 0.2 µM The results confirm the potent inhibitory effects of E6080 on the release of LTs.

Inhibition of IgE-Mediated Leukotriene Generation and Bronchoconstriction in Primates with a New 5-Lipoxygenase Inhibitor, E6080

“…In contrast, low re sponder monkeys did not show significant changes in R, or Cdyn. 1 [iM), but higher than those of human lung frag ments (0.2 \jM ) [14]. AA861, which is also a potent and se lective 5-lipoxygenase inhibitor [27], showed similar inhib itory activity on LTC4 generation in lung fragments to E6080.…”

“…In this study, the effects of a newly synthesized and orally active 5-lipoxygcnase inhibitor, 6-hydroxy-2-(4-sulfamoylbcnzylamino)-4,5,7-trimethylbenzothiazolc hydro chloride (E6080) [14][15][16][17], were determined on IgE-mcdiated reactions in rhesus monkey models in vitro and in vivo.…”