Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites?

Aspirin and salicylate are transformed by stimulated human polymorphonuclear leucocytes (PMN), likely to be found at inflammatory sites, into both 2,3- and 2,5-dihydroxybenzoates (DHB). These DHB inhibit both the production of hydrogen peroxide by stimulated human PMN and prostaglandin (PG) E2 by activated rat macrophages. In contrast, DHB stimulated production of interleukin (IL)-1 and tumour necrosis factor (TNF) but inhibited IL-6 production by rat macrophages. These effects were probably a consequence of PGE2 inhibition. Gentisate (2,5-DHB) and homogentisate (a tyrosine metabolite) inhibited the lymphoproliferative action of IL-1. Some related phenols, e.g. 5-aminosalicylate, inhibited H2O2 production but had little effect on PGE2 production. These findings suggest that the local synthesis of DHB may contribute to the overall anti-inflammatory activity of salicylate, which (unlike aspirin) has little direct effect on PG production.