Effects of the new 5-lipoxygenase inhibitor E6080 on leukotriene release in vitro.
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 mM L-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 LTC4 release from passively sensitized human (IC50: LTB4 0.08 microM, LTC4 0.2 microM) and guinea-pig lung fragments (IC50: LTC4 1.1 microM). The LTB4 and LTC4 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 microM. Furthermore, the LTC4 release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC50 of 0.2 microM. 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 microM. The results confirm the potent inhibitory effects of E6080 on the release of LTs.
Sakuma
Y
Y
Department of Pharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Katayama
S
S
Tsunoda
H
H
Abe
S
S
Yamatsu
I
I
Katayama
K
K
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001491:Basophils / Q000187:drug effects / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D013189:SRS-A / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
D016227:Benzoquinones; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D013844:Thiazoles; C064507:E 6080; D007975:Leukotriene B4; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase