{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:30:55Z","timestamp":1791156655801,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,8,27]],"date-time":"2007-08-27T00:00:00Z","timestamp":1188172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL 68758"],"award-info":[{"award-number":["P01 HL 68758"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG027080"],"award-info":[{"award-number":["R01 AG027080"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL081738"],"award-info":[{"award-number":["P01 HL081738"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:p>\n                    The primary pharmacological target of acetaminophen is prostaglandin endoperoxide H\n                    <jats:sub>2<\/jats:sub>\n                    syn\u2010thase (PGHS). The enzymatic catalytic mechanism is radical\u2010based, initiated, and maintained by the persistent presence of peroxides, particularly peroxynitrite, which is termed \u201cperoxide tone\u201d. 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\u2010mediated phenol nitration, IC\n                    <jats:sub>50<\/jats:sub>\n                    \u224872\u03bcM; Sin\u20101\u2010mediated DHR123 oxidation, IC\n                    <jats:sub>50<\/jats:sub>\n                    \u224811\u03bcM) 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\n                    <jats:sub>50<\/jats:sub>\n                    \u224810\u03bcM for 6\u2010keto\u2010PGF\n                    <jats:sub>1\u03b1<\/jats:sub>\n                    ) and other free radical scavengers. However, when the peroxide tone was provided by H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    or tert\u2010butyl\u2010OOH, 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\u2010inflammatory effects.\u2014 Schildknecht, S., Daiber, A., Ghisla, S., Cohen, R. A., Bachschmid, M. M. Acetaminophen inhibits prostanoid synthesis by scavenging the PGHS\u2010activator peroxynitrite.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    22, 215\u2013224 (2008)\n                  <\/jats:p>","DOI":"10.1096\/fj.06-8015com","type":"journal-article","created":{"date-parts":[[2007,8,27]],"date-time":"2007-08-27T20:39:23Z","timestamp":1188247163000},"page":"215-224","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Acetaminophen inhibits prostanoid synthesis by scavenging the PGHS\u2010activator peroxynitrite"],"prefix":"10.1096","volume":"22","author":[{"given":"Stefan","family":"Schildknecht","sequence":"first","affiliation":[{"name":"Vascular Biology Unit Whitaker Cardiovascular Institute Boston University School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Daiber","sequence":"additional","affiliation":[{"name":"Department of Cardiology Johannes Gutenberg University Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Ghisla","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Konstanz Konstanz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Vascular Biology Unit Whitaker Cardiovascular Institute Boston University School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus M.","family":"Bachschmid","sequence":"additional","affiliation":[{"name":"Vascular Biology Unit Whitaker Cardiovascular Institute Boston University School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,8,27]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1973.sp010071"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1973.sp010346"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10543"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/35011103"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1988.tb13793.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324143"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-2797(88)90101-9"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(78)90367-2"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-6980(89)90001-4"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00613.2004"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2437fje"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2005.09.009"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(82)90565-2"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003950170023"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1099-1271(199811\/12)13:6<339::AID-BIO501>3.0.CO;2-E"},{"key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/S0021-9258(19)75736-6","article-title":"The 1\u2010 and 2\u2010electron oxidation of acetaminophen catalyzed by prostaglandin H synthase","volume":"262","author":"Potter D. 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