Inammopharmacology , Vol. 9, No. 1,2, pp. 131–142 (2001) Ó VSP 2001. Inhibition of prostaglandin synthesis in intact cells by paracetamol (acetaminophen) GARRY G. GRAHAM 1;3;¤ , SALLY-ANNE ROBINS 1;3 , KATHERINE J. BRYANT 2;3 and KIERAN F. SCOTT 2;3 1 School of Physiology and Pharmacology, Faculty of Medicine, University of New South Wales, UNSW Sydney 2052 2 School of Medicine, Faculty of Medicine, University of New South Wales, UNSW Sydney 2052 3 The Arthritis and Inammation Research Program, Garvan Research Institute, Darlinghurst 2010, NSW, Australia Received 16 November 2000; accepted 23 November 2000 Abstract —Despite its wide use, the mechanism of action of paracetamol (acetaminophen) is uncertain. It is commonly stated to be a weak inhibitor of the synthesis of prostaglandins (PGs) by the prostaglandin H synthases (COX-1 and COX-2) but paracetamol inhibits the synthesis of PGs in stimulated cultured cells with IC 50 values ranging from 4 to 200 ¹M. Paradoxically, it generally stimulates PG production in broken cell preparations. Here we show that paracetamol inhibits the production of PGs in human rheumatoid synoviocytes during stimulation by interleukin- 1¯ (0.1ng/ml) for 18 h. Paracetamol inhibited the production of both PGE 2 and PGF 2® with median IC 50 values of 7.2 and 4.2 ¹M respectively, without affecting the or the level of the constitutive enzyme, COX-1 or the interleukin-1 ¯ mediated induction of both COX-2 and cytosolic phospholipase A 2 -® (cPLA 2 -® ). These data indicate that paracetamol suppresses delayed PG production by direct modulation of the cPLA 2 -® /COX-2 pathway at therapeutic concentrations. Paracetamol is a substituted phenol and its effects on the synthesis of PGs are very similar to those of other phenols. Paracetamol should be considered to inhibit the production of PGs although the cause of its selectivity; analgesic and antipyretic effects with weak antiplatelet and anti-inammatory effects is unknown. Key words: Paracetamol; acetaminophen; phenol; eugenol; rheumatoid arthritis; cyclooxygenase-2; prostaglandin E 2 ; prostaglandin F 2® . ¤ To whom correspondence should be addressed. Prof. G. G. Graham, School of Physiology and Pharmacology, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. E-mail: g.graham@unsw.edu.au