Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma, Nara 630-0101, Japan.
Biol Pharm Bull. 2010;33(6):1050-3. doi: 10.1248/bpb.33.1050.
We investigated the role of leukotriene (LT) B(4) in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses using SA6541, an LTA(4) hydrolase inhibitor. Itch-associated responses were induced by intradermal injection of 5-hydroperoxyeicosatetraenoic acid (HPETE), a precursor of 5-lipoxygenase metabolites, and passive cutaneous anaphylaxis in ICR mice. By screening molecules related to arachidonic acid metabolism or pruritus, SA6541 was found to be a specific inhibitor of LTA(4) hydrolase. Pharmacokinetic studies confirmed the specificity of SA6541 at an oral dose of 100 mg/kg in mice. 5-HPETE induced scratching behavior, which was inhibited by SA6541 (100 mg/kg). However, SA6541 (100 mg/kg) hardly attenuated the 5-HPETE-induced increase in vascular permeability. Moreover, SA6541 (100 mg/kg) partially attenuated scratching behavior, but did not affect the increase in vascular permeability caused by passive cutaneous anaphylaxis. On the other hand, ketotifen fumarate, a histamine H1 antagonist, strongly inhibited the scratching behavior and the increase in vascular permeability caused by passive cutaneous anaphylaxis. These results suggest that LTB(4) is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions.
我们使用 LTA4 水解酶抑制剂 SA6541 研究了白三烯 (LT) B4 在 5-脂氧合酶代谢物和过敏引起的瘙痒相关反应中的作用。瘙痒相关反应是通过向 ICR 小鼠皮内注射 5-过氧二十碳四烯酸 (HPETE)（5-脂氧合酶代谢物的前体）和被动皮肤过敏反应诱导的。通过筛选与花生四烯酸代谢或瘙痒相关的分子，发现 SA6541 是 LTA4 水解酶的特异性抑制剂。药代动力学研究证实，SA6541 在 100mg/kg 口服剂量时在小鼠中具有特异性。5-HPETE 诱导搔抓行为，SA6541（100mg/kg）可抑制该行为。然而，SA6541（100mg/kg）几乎不能减轻 5-HPETE 引起的血管通透性增加。此外，SA6541（100mg/kg）部分减轻搔抓行为，但不影响被动皮肤过敏反应引起的血管通透性增加。另一方面，组胺 H1 拮抗剂富马酸酮替芬强烈抑制被动皮肤过敏反应引起的搔抓行为和血管通透性增加。这些结果表明 LTB4 是皮肤中的内源性瘙痒介质，参与过敏反应中的瘙痒反应。
