IS ASPIRIN A PRODRUG FOR ANTIOXIDANT AND CYTOKINE-MODULATING OXYMETABOLITES

Aspirin and salicylate are transformed by stimulated human polymorphon uclear leucocytes (PMN), likely to be found at inflammatory sites, int o both 2,3- and 2,5-dihydroxybenzoates (DHB). These DHB inhibit both t he production of hydrogen peroxide by stimulated human PMN and prostag landin (PG) E2 by activated rat macrophages. In contrast, DHB stimulat ed production of interleukin (IL)-1 and tumour necrosis factor (TNF) b ut inhibited IL-6 production by rat macrophages. These effects were pr obably a consequence of PGE2 inhibition. Gentisate (2,5-DHB) and homog entisate (a tyrosine metabolite) inhibited the lymphoproliferative act ion of IL-1. Some related phenols, e.g. 5-aminosalicylate, inhibited H 2O2 production but had little effect on PGE2 production. These finding s suggest that the local synthesis of DHB may contribute to the overal l anti-inflammatory activity of salicylate, which (unlike aspirin) has little direct effect on PG production.