Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells.

Sciulli, Maria G.; Seta, Francesca; Tacconelli, Stefania; Capone, Marta L; Ricciotti, Emanuela

1 Acetaminophen, an analgesic and antipyretic drug with weak antiinflammatory properties, has been suggested to act as a tissue-selective inhibitor of prostaglandin H synthases (PGHSs) (e.g. COX-1 and COX-2) through its reducing activity, that is influenced by the different cellular levels of peroxides. 2 We have studied the effects of acetaminophen on inducible and constitutive prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate between the inhibitory effect of the drug on PGHS-isozymes vs PGE-synthases (PGESs), parallel measurements of PGE[sub 2] and thromboxane (TX) B[sub 2] were carried out. Since antioxidant enzymes and cofactors, present in plasma, may affect acetaminophen-dependent inhibition of prostanoids, comparative experiments in whole blood vs isolated monocytes were performed. 3 Acetaminophen inhibited LPS-induced whole blood PGE[sub 2] and TXB[sub 2] production, in a concentration-dependent fashion [IC[sub 50] µM (95% confidence intervals): 44 (27-70) and 94 (79112), respectively]. Therapeutic plasma concentrations (100 and 300 µm) of the drug more profoundly reduced PGE[sub 2] than TXB2 (71±3 vs 54±4 and 95±0.8 vs 78±2%, respectively, mean ± s.e.mean, n=6, P<0.01). 4 Differently, in isolated monocytes stimulated with LPS, both PGE[sub 2] and TXB[sub 2] production was maximally reduced by only 60%. 5 At 100 and 300 µM, the drug caused a similar and incomplete inhibition of platelet PGE[sub 2] and TXB[sub 2] production during whole blood clotting (45 ± 4 vs 54 ± 4 and 75 ± 2 vs 75 ± 1%, respectively, mean ± s.e.mean, n = 4). 6 In conclusion, therapeutic concentrations of acetaminophen caused an incomplete inhibition of platelet COX-1 and monocyte COX-2 but in the presence of plasma, the drug almost completely suppressed inducible PGE[sub 2] biosynthesis through its inhibitory effects on both COX-2 and inducible PGES.

ACETAMINOPHEN; BIOSYNTHESIS; BLOOD cells

British Journal of Pharmacology, 2003, Vol 138, Issue 4, p634

0007-1188

Academic Journal

10.1038/sj.bjp.0705078