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Acetaminophen inhibits prostanoid synthesis by scavenging the PGHS‐activator peroxynitrite
Author(s) -
Schildknecht Stefan,
Daiber Andreas,
Ghisla Sandro,
Cohen Richard A.,
Bachschmid Markus M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-8015com
Subject(s) - peroxynitrite , chemistry , acetaminophen , nitric oxide , prostacyclin , biochemistry , ic50 , prostanoid , pharmacology , enzyme , prostaglandin , superoxide , in vitro , organic chemistry , medicine
The primary pharmacological target of acetaminophen is prostaglandin endoperoxide H 2 syn‐thase (PGHS). The enzymatic catalytic mechanism is radical‐based, initiated, and maintained by the persistent presence of peroxides, particularly peroxynitrite, which is termed “peroxide tone”. Whereas the prevailing concept assumes a direct reduction of the active, oxidized enzyme by acetaminophen, here we show that acetaminophen is a potent scavenger of peroxynitrite (peroxynitrite‐mediated phenol nitration, IC 50 ≈72μM; Sin‐1‐mediated DHR123 oxidation, IC 50 ≈11μM) and thus inhibits PGHS by eliminating the peroxide tone. Nanomolar concentrations of peroxynitrite increased the activity of isolated PGHS and prostacyclin formation by aortic endothelial cells. This elevated activity was efficiently inhibited by pharmacologically relevant concentrations of acetaminophen (IC 50 ≈10μM for 6‐keto‐PGF 1α ) and other free radical scavengers. However, when the peroxide tone was provided by H 2 O 2 or tert‐butyl‐OOH, acetaminophen had only negligible inhibitory effects. Our concept could help to explain the efficacy of acetaminophen to inhibit PGHS in cell types with moderate oxidant formation. However, high levels of peroxynitrite or other peroxides such as lipid peroxides formed at inflammatory sites might overwhelm the ability of acetaminophen to decrease PGHS activation. The concept presented herein provides a molecular basis to explain the excellent analgesic and antipyretic properties of acetaminophen together with its minimal anti‐inflammatory effects.— Schildknecht, S., Daiber, A., Ghisla, S., Cohen, R. A., Bachschmid, M. M. Acetaminophen inhibits prostanoid synthesis by scavenging the PGHS‐activator peroxynitrite. FASEB J. 22, 215–224 (2008)