Actions of paracetamol on cyclooxygenases in tissue and cell homogenates of mouse and rabbit.
BACKGROUND
Paracetamol is a potent analgesic and antipyretic drug, but has only weak anti-inflammatory activity. Unlike aspirin-like drugs, paracetamol does not damage the stomach mucosa or inhibit the aggregation of platelets. The analgesic action of paracetamol is on the central nervous system. In vitro, paracetamol inhibits cyclooxygenase (COX)-1 and -2 in high concentrations but stimulates in low doses. This study examines the stimulation and inhibition of COX-1 and COX-2 in homogenates of mouse and rabbit tissues and in J774.2 cultured mouse macrophages.


METHODS
Mouse and rabbit tissues were removed, homogenised and treated with different concentrations of paracetamol. Prostaglandins (PGs) E2 and I2 were measured in the homogenates to assess the activity of COX-1. Ex vivo synthesis of PGE2 was measured in tissues after treating rabbits with 100 mg/kg paracetamol. J774.2 cultured mouse macrophages treated with bacterial lipopolysaccharide (LPS) to induce COX-2, were treated with varying concentrations of paracetamol and the PGs produced were measured.


RESULTS
Low doses of paracetamol stimulated PG production in J774.2 macrophages and stomach mucosa homogenates, but reduced PG production at high concentrations of paracetamol. This stimulation did not occur when co-factors were added. The order of potency of paracetamol on COX-1 or COX-2 in tissue homogenates was as follows: lungs>spleen>brain>J774.2 cells>stomach mucosa. Paracetamol, 100 mg/kg, inhibited COX-1 in stomach mucosa ex vivo much less effectively than in other tissues.


CONCLUSIONS
These data support the hypothesis that paracetamol selectively inhibits a COX enzyme which is different from COX-1 or COX-2 and may be a variant of COX-1.
Swierkosz
Tomasz A
TA
The William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.
Jordan
Lynne
L
McBride
Melissa
M
McGough
Kevin
K
Devlin
Jean
J
Botting
Regina M
RM
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D013154:Spleen / Q000187:drug effects / Q000201:enzymology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D000082:Acetaminophen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse