title: Effects of paracetamol on NOS, COX, and CYP activity and on oxidative stress in healthy male subjects, rat hepatocytes, and recombinant NOS.
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 F(1α), respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-prostaglanding F(2α) 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.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Trettin
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Böhmer
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Maria-Theresia
authors.initials: MT
authors.lastname: Suchy
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Georg-August University, 37073 Goettingen, Germany.
authors.forename: Irmelin
authors.initials: I
authors.lastname: Probst
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Staerk
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Dirk O
authors.initials: DO
authors.lastname: Stichtenoth
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Frölich
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Dimitrios
authors.identifier: 0000-0001-6320-0956
authors.initials: D
authors.lastname: Tsikas
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013931:Thromboxanes / Q000096:biosynthesis
chemical_list: D011994:Recombinant Proteins; D013931:Thromboxanes; D009569:Nitric Oxide; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases