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J Pharmacol Exp Ther. 2005 Oct;315(1):1-7. Epub 2005 May 6.

Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties.

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  • 1Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA.


Cyclooxygenase (COX)-3, a novel COX splice variant, was suggested as the key to unlocking the mystery of the mechanism of action of acetaminophen. Although COX-3 might have COX activity in canines, and this activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance. In rodents and humans, COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity; therefore, it is improbable that COX-3 in these species plays a role in prostaglandin-mediated fever and pain. The aim of this review is to evaluate the literature that seeks to point out critical theoretical and methodological limitations of the COX-3 studies that led several investigators to scientifically questionable conclusions.

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