{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T05:17:22Z","timestamp":1770959842367,"version":"3.50.1"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":9619,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1989,5]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Isaxonine and several other drugs transformed by cytochrome P-450 into reactive metabolites apparently lead to immunoallergic hepatitis in man. Protein epitopes modified by the covalent binding of the metabolites have been proposed as possible targets for the immune response. The purpose of this work was to determine whether covalently bound metabolites are indeed present on hepatocyte plasma membrane proteins. In a first series of experiments, rats were killed 15 or 60 min after administration of [2-<jats:sup>14<\/jats:sup>C]isaxonine (0.2 mmole \u00b7 kg<jats:sup>\u22121<\/jats:sup> i.p.), and various fractions were prepared from isolated hepatocytes; microsomal contamination of the plasma membrane fraction was 1.2% or less. At 60 min, the amount of isaxonine metabolite covalently bound per mg of protein was similar in plasma membranes (0.42 nmole metabolite \u00b7 mg protein<jats:sup>\u22121<\/jats:sup>) and in microsomes (0.38); both values were decreased by about 70% in rats pretreated with piperonyl butoxide, an inhibitor of cytochrome P-450. At 15 min, however, covalent binding to plasma membrane proteins (0.06 nmole metabolite \u00b7 mg protein<jats:sup>\u22121<\/jats:sup>) was only half of that to microsomal proteins (0.12). In a second series of experiments, [2-<jats:sup>14<\/jats:sup>C] isaxonine (0.1 m<jats:italic toggle=\"yes\">M<\/jats:italic>) was incubated with NADPH, hepatic microsomes and plasma membranes. The reactive isaxonine metabolite became bound extensively to microsomal proteins, but not to plasma membrane proteins. These results show that administration of isaxonine leads to the presence of isaxonine adducts on the proteins of the hepatocyte plasma membrane. They are consistent with the <jats:italic toggle=\"yes\">in situ<\/jats:italic> binding of a highly unstable metabolite in the endoplasmic reticulum, or its immediate vicinity, some of these proteins then migrating toward the plasma membrane <jats:italic toggle=\"yes\">in vivo<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.1840090503","type":"journal-article","created":{"date-parts":[[2007,3,3]],"date-time":"2007-03-03T23:11:16Z","timestamp":1172963476000},"page":"675-678","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":21,"title":["Presence of covalently bound metabolites on rat hepatocyte plasma membrane proteins after administration of isaxonine, a drug leading to immunoallergic hepatitis in man"],"prefix":"10.1097","volume":"9","author":[{"given":"Jacqueline","family":"Loeper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e9ronique","family":"Descatoire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilles","family":"Amouyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Lett\u00e9ron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Larrey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Pessayre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"10.1002\/hep.1840090503-BIB1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1056\/NEJM198007103030202","volume":"303","author":"Vergani","year":"1980","journal-title":"N Engl J Med"},{"key":"10.1002\/hep.1840090503-BIB2","first-page":"857","volume":"233","author":"Satoh","year":"1985","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1002\/hep.1840090503-BIB3","first-page":"468","volume":"28","author":"Satoh","year":"1985","journal-title":"Mol Pharmacol"},{"key":"10.1002\/hep.1840090503-BIB4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/10408448509037460","volume":"14","author":"Guengerich","year":"1985","journal-title":"CRC Crit Rev Toxicol"},{"key":"10.1002\/hep.1840090503-BIB5","first-page":"352","volume":"7","author":"Baud","year":"1983","journal-title":"Gastroenterol Clin Biol"},{"key":"10.1002\/hep.1840090503-BIB6","first-page":"845","volume":"229","author":"Lett\u00e9ron","year":"1984","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1002\/hep.1840090503-BIB7","first-page":"851","volume":"229","author":"Fouin-Fortunet","year":"1984","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1002\/hep.1840090503-BIB8","first-page":"29","volume-title":"Methods in cell biology","author":"Seglen","year":"1976","unstructured":"Preparation of isolated rat liver cells. 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