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INFLAMMATION AND IMMUNOPHARMACOLOGY

Cyclooxygenases 1, 2, and 3 and the Production of Prostaglandin I₂: Investigating the Activities of Acetaminophen and Cyclooxygenase-2-Selective Inhibitors in Rat Tissues

The William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom (T.D.W., I.V., F.G., R.J., D.B.-B.); and Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Imperial College London, Royal Brompton Hospital, London, United Kingdom (J.A.M.)

It has been suggested recently that cyclooxygenase-3, formed as a splice variant of cyclooxygenase-1, is the enzymatic target for acetaminophen. To investigate the relative roles of the putative three cyclooxygenase isoforms in different target tissues, we compared the inhibitory effects of acetaminophen, a cyclooxygenase-2-selective inhibitor; rofecoxib, a nonsteroid anti-inflammatory drug; naproxen; and a cyclooxygenase-1-selective inhibitor, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]. Prostanoid production by aorta, heart, lung, and whole blood was inhibited by all drugs tested with the order of potency SC560 > naproxen > acetaminophen rofecoxib. In brain and cerebellum, no differences among drug potencies were found. Reverse transcription-polymerase chain reaction analysis of aorta, brain, cerebellum, heart, and lung showed general expression of cyclooxygenase-1 and cyclooxygenase-3 mRNA and particular expression of cyclooxygenase-2 mRNA in brain and cerebellum. Western blotting demonstrated general expression of cyclooxygenase-1 in test tissues and cyclooxygenase-2 within the brain and cerebellum. Western blotting using a commercially available antibody raised against canine cyclooxygenase-3 failed to detect any immunoreactive proteins. In conclusion, our studies indicate that cyclooxygenase-1 and cyclooxygenase-2 are the functional forms of the enzyme present in the rat tissues tested and that acetaminophen is not a selective inhibitor of "cyclooxygenase" activities in the central nervous system. This is consistent with the apparent impossibility for the expression of cyclooxygenase active protein from cyclooxygenase-3 mRNA in the rat. Also, our experiments show that the ability of rofecoxib to depress the circulating levels of prostaglandin I₂ is more readily associated with its ability to reduce production from the lung, heart, or brain than from arterial vessels.

Address correspondence to: Prof. Timothy D. Warner, The William Harvey Research Institute, Barts and the London, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail: t.d.warner{at}qmul.ac.uk

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