CAFFEIC ACID IS A SELECTIVE INHIBITOR FOR LEUKOTRIENE BIOSYNTHESIS

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 792  (1) , 92-97
Abstract
Leukotrienes [LT] are significantly involved in immunoregulation and in a variety of [human] diseases, including asthma, inflammation and various allergic conditions. They are initially biosynthesized by 5-lipoxygenase from arachidonic acid, which can also be metabolized to prostaglandin endoperoxide by cyclooxygenase. The specific inhibitors for 5-lipoxygenase would be useful not only as tools for investigating the regulation mechanism of LT biosynthesis but also as drugs for clinical use. Although recently a few selective inhibitors have been reported, most of them are difficult to obtain since they are new compounds. Caffeic acid, a common reagent, is a selective inhibitor for 5-lipoxygenase and thus for LT biosynthesis. The inhibitory effect of its methyl ester on 5-lipoxygenase (ID50 [median inhibitory dose] = 4.8 .cntdot. 10-7 M) was stronger than that of caffeic acid itself (ID50 = 3.7 .cntdot. 10-6 M). Caffeic acid inhibited 5-lipoxygenase in a non-competitive manner. Caffeic acid and its methyl ester did not inhibit prostaglandin synthase activity at all, at least up to 5 .cntdot. 10-4 M, but rather stimulated at higher doses. The biosynthesis of LT C4 and D4 in mouse mast tumor cells was also inhibited completly with 10-4 caffeic acid. Besides, caffeic acid had little effect on arachidonic acid metabolism in platelet at < 1 .cntdot. 10-5 M, but, at higher doses, it showed a definite inhibitory effect, i.e., thromboxane B2, HHT [12(S)-hydroxy-5,8,10-heptadecatetraenoic acid] and 12-HETE [12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid] syntheses were inhibited 33, 40 and 80% at 1 .cntdot. 10-4 M, respectively. Platelet aggregation induced by arachidonic acid was also inhibited by caffeic acid at high dose while platelet aggregation induced by ADP is not influenced by caffeic acid at all. The observations on caffeic acid and its derivatives may contribute to LT research.