Cyclooxygenase (COX) enzymes (COX)

Acetaminophen primarily exerts its analgesic and antipyretic effects through weak inhibition of cyclooxygenase (COX) enzymes, particularly in the brain and spinal cord, reducing prostaglandin synthesis that mediates pain and fever. Unlike NSAIDs, it has minimal peripheral anti-inflammatory activity, possibly due to selective action on a COX-3 variant or central mechanisms. The drug is metabolized mainly in the liver via glucuronidation (UGT1A1, UGT1A6, UGT1A9, UGT2B15) and sulfation (SULT1A1, SULT1A3/4), with a minor oxidative pathway via cytochrome P450 enzymes (primarily CYP2E1, also CYP1A2, CYP2A6, CYP3A4 at high doses) producing the reactive metabolite NAPQI. NAPQI is normally detoxified by glutathione conjugation (via GSTP1, GSTT1, GSTM1), but overdose depletes glutathione, causing hepatotoxicity. Additional mechanisms involve metabolites like AM404 activating TRPV1 and CB1 receptors for analgesia. No single receptor defines acetaminophen's action; it is not developed as a direct therapeutic target but interacts with COX and metabolic enzymes, with toxicity risks limiting dosing.

Other names

Prostaglandin G/H synthase 1 (PTGS1)Prostaglandin G/H synthase 2 (PTGS2)Cyclooxygenase-1Cyclooxygenase-2COX-1COX-2COX-3 (speculative variant)

Inhibition of COX enzymes in brain and spinal cord to reduce prostaglandin production, lowering pain and fever. Possible central action on COX-3 variant. Metabolite AM404 activation of TRPV1 and CB1 receptors.