Inhibitory activity of a series of coumarins on leukocyte eicosanoid generation.
Sixteen plant-derived or synthetic coumarins with different patterns of substitution were tested for their capacity to modify A23187-induced synthesis of leukotriene B4 and thromboxane B2 via the 5-lipoxygenase and cyclooxygenase pathways of arachidonate metabolism in rat peritoneal exudate leukocytes. Five of the 16 coumarins inhibited LTB4 production: all contain orthodihydroxy substitutions (approximate IC50 values 8-100 microM). The mechanism is likely to depend upon a combination of the coumarins' iron-chelating and iron ion-reducing abilities, properties which also confer beneficial activities of these compounds as scavengers of reactive oxygen species (Payá et al., Biochem. Pharmacol. 44, 205-214 (1992)). Inhibition of the cyclooxygenase pathway was only demonstrated by one compound, 5,7-dihydroxy-4-methylcoumarin, which did not inhibit 5-lipoxygenase, indicating that the cyclooxygenase inhibitory mechanism is different. Similar effects of the active coumarins were obtained using arachidonic acid as substrate for rat leukocyte eicosanoid generation, confirming that they act at the 5-lipoxygenase/cyclooxygenase level. The same profile of activity was also shown when the coumarins were tested against 5-lipoxygenase in human polymorphonuclear neutrophils. Taken together, these antioxidant and anti-eicosanoid properties of coumarins could be exploited for the design of potentially valuable non-toxic anti-inflammatory agents for treating diseases in which eicosanoid generation and the production of reactive oxygen species are involved.
Hoult
J R
JR
Pharmacology Group, King's College London, UK.
Forder
R A
RA
de las Heras
B
B
Lobo
I B
IB
Payá
M
M
D000818:Animals; D000001:Calcimycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003864:Depression, Chemical; D015777:Eicosanoids / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis
D003374:Coumarins; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D017382:Reactive Oxygen Species; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2