{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:01:58Z","timestamp":1791050518579,"version":"4.1.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,11,7]]},"abstract":"<jats:p>\n                    Overdose of acetaminophen, a widely used analgesic drug, can result\n in severe hepatotoxicity and is often fatal. This toxic reaction is\n associated with metabolic activation by the P450 system to form a\n quinoneimine metabolite,\n                    <jats:italic>N<\/jats:italic>\n                    -acetyl-\n                    <jats:italic>p<\/jats:italic>\n                    -benzoquinoneimine (NAPQI),\n which covalently binds to proteins and other macromolecules to cause\n cellular damage. At low doses, NAPQI is efficiently detoxified,\n principally by conjugation with glutathione, a reaction catalyzed in\n part by the glutathione\n                    <jats:italic>S<\/jats:italic>\n                    -transferases (GST), such as\n GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we\n examined acetaminophen metabolism and liver damage in mice nulled for\n GstP (\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(\u2212\/\u2212)<\/jats:sup>\n                    ). Contrary to our\n expectations, instead of being more sensitive, GstP null mice were\n highly resistant to the hepatotoxic effects of this compound. No\n significant differences between wild-type\n (\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(+\/+)<\/jats:sup>\n                    ) mice and\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(\u2212\/\u2212)<\/jats:sup>\n                    nulls in either the rate\n or route of metabolism, particularly to glutathione conjugates, or in\n the levels of covalent binding of acetaminophen-reactive metabolites to\n cellular protein were observed. However, although a similar rapid\n depletion of hepatic reduced glutathione (GSH) was found in both\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(+\/+)<\/jats:sup>\n                    and\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(\u2212\/\u2212)<\/jats:sup>\n                    mice, GSH levels only\n recovered in the\n                    <jats:italic>GstP1\/P2<\/jats:italic>\n                    <jats:sup>(\u2212\/\u2212)<\/jats:sup>\n                    mice.\n These data demonstrate that GstP does not contribute\n                    <jats:italic>in\n vivo<\/jats:italic>\n                    to the formation of glutathione conjugates of\n acetaminophen but plays a novel and unexpected role in the toxicity of\n this compound. This study identifies new ways in which GST can modulate\n cellular sensitivity to toxic effects and suggests that the level of\n GST Pi may be an important and contributing factor in the sensitivity\n of patients with acetaminophen-induced hepatotoxicity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.220176997","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:45:09Z","timestamp":1027680309000},"page":"12741-12745","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":190,"title":["Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione\n                    <i>S<\/i>\n                    -transferase Pi"],"prefix":"10.1073","volume":"97","author":[{"given":"Colin J.","family":"Henderson","sequence":"first","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Roland","family":"Wolf","sequence":"additional","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Kitteringham","sequence":"additional","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Powell","sequence":"additional","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Otto","sequence":"additional","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Kevin","family":"Park","sequence":"additional","affiliation":[{"name":"Imperial Cancer Research Fund Molecular Pharmacology Unit,\r Biomedical Research Centre, Level 5, Ninewells Hospital and Medical\r School, Dundee, DD1 9SY, United Kingdom; and Department\r of Pharmacology and Therapeutics, University of Liverpool, New Medical\r Building, Ashton Street, Liverpool, L69 3GE, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,10,31]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"898","volume":"7","author":"Villeneuve J P","year":"1983","unstructured":"J P Villeneuve, G Raymond, J Bruneau, L Colpron, G Pomier-Layrargues Gastroenterol Clin Biol 7, 898\u2013902 (1983).","journal-title":"Gastroenterol Clin 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