[jinx]

Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties

Received February 24, 2005; accepted May 5, 2005.

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....

In 2002, Dan Simmons' group reported the discovery of a new COX isoenzyme that was putatively the specific target of acetaminophen. The discovery of the so-called COX-3 as an acetaminophen-sensitive isoform seemed to solve the mystery of acetaminophen and attracted considerable attention, and several commentaries were published quickly in prominent scientific journals. This discovery in canines was generalized to humans and rodents without critical evaluation of the experimental data. Unfortunately, many in the scientific community now believe that the mechanism of action of acetaminophen is selective inhibition of COX-3; however, this hypothesis is not supported by experimental evidence. The aim of this review is to thoroughly evaluate the scientific literature with particular examination of the critical theoretical and methodological contradictions of the COX-3 puzzle.