Abstract
Paracetamol (acetaminophen) is a widely used analgesic drug. It interacts with various enzyme families including cytochrome P450 (CYP), cyclooxygenase (COX), and nitric oxide synthase (NOS), and this interplay may produce reactive oxygen species (ROS). We investigated the effects of paracetamol on prostacyclin, thromboxane, nitric oxide (NO), and oxidative stress in four male subjects who received a single 3 g oral dose of paracetamol. Thromboxane and prostacyclin synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1α, respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-prostaglanding F2α was measured to assess oxidative stress. Plasma oleic acid oxide (cis-EpOA) was measured as a marker of cytochrome P450 activity. Upon paracetamol administration, prostacyclin synthesis was strongly inhibited, while NO synthesis increased and thromboxane synthesis remained almost unchanged. Paracetamol may shift the COX-dependent vasodilatation/vasoconstriction balance at the cost of vasodilatation. This effect may be antagonized by increasing endothelial NO synthesis. High-dosed paracetamol did not increase oxidative stress. At pharmacologically relevant concentrations, paracetamol did not affect NO synthesis/bioavailability by recombinant human endothelial NOS or inducible NOS in rat hepatocytes. We conclude that paracetamol does not increase oxidative stress in humans.
Highlights
Nitric oxide (NO), prostaglandin (PG) I2, that is, prostacyclin (PGI2), and thromboxane A2 (TxA2) are important short-lived signaling molecules involved in many physiological and pathological processes
By using paracetamol concentrations that are expected to prevail for a considerable period of time after administration of a single 3 g oral dose to humans, we investigated the effects of paracetamol at suprapharmacological concentrations on the activity of two NO synthase (NOS) isoforms in vitro, that is, on recombinant human endothelial NOS (eNOS) and inducible NOS (iNOS) in rat hepatocytes
We investigated in vitro and in vivo effects of paracetamol, an analgesic and antipyretic phenolic drug, on the L-Arg/NO, arachidonic acid (AA)/COX, and cytochrome P450 (CYP) biochemical pathways and on oxidative stress
Summary
Nitric oxide (NO), prostaglandin (PG) I2, that is, prostacyclin (PGI2), and thromboxane A2 (TxA2) are important short-lived signaling molecules involved in many physiological and pathological processes. The inducible NOS (iNOS) isoform has been shown to bind to the inducible COX isoform (COX-2) and to S-nitrosylate and activate COX-2 [2]. Potential mechanisms of direct NOS-COX cross-talk may include (1) binding of NO to the iron atom of the heme group of COX, (2) reaction of the nitrosyl cation (NO+) with sulfhydryl (SH) groups of cysteine (Cys) moieties of COX to form S-nitroso-COX, and (3) reaction of peroxynitrite (ONOO−), that is, the reaction product of NO radical (∙NO) and superoxide radical anion (O2∙−) produced either by NOS itself or by other enzymes including COX and CYP [3], with SH groups of Cys residues or with tyrosine (Tyr) residues of COX being involved in the catalytic process [2]. S-Nitrosylation of COX-Cys moieties by higher oxides of NO, notably dinitrogen trioxide (N2O3), and Oxidative Medicine and Cellular Longevity by ONOO− and S-transnitrosylation of COX-Cys moieties by low-molecular-mass S-nitrosothiols have been shown to both enhance and inhibit COX activity. ONOO− has been reported to enhance COX activity presumably by increasing the peroxide concentration that is required for the peroxidase activity of COX [7]
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