{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T15:15:59Z","timestamp":1776179759885,"version":"3.50.1"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":5509,"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":[[2000,8]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Exposure of cells to toxic chemical species can result in reduced glutathione (GSH) depletion, generation of free radicals, and\/or binding to critical cell determinants. Chemical stress is usually followed by a concerted cellular response aimed at restoring homeostasis, although the precise initial stimulus for the response is unclear. We have focused on one component of this stress response, the up-regulation of \u03b3-glutamylcysteine synthetase (\u03b3-GCS) and the preceding molecular events involved in its regulation in an <jats:italic toggle=\"yes\">in vivo<\/jats:italic> mouse model. Male CD-1 mice received buthionine sulphoximine (BSO; 7.2 mmol\/kg), diethyl maleate (DEM; 4.2 mmol\/kg), paracetamol (APAP; 3.5 and 1.0 mmol\/kg), or carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>; 1.0 and 0.2 mmol\/kg). Biochemical (serum transaminase and hepatic GSH levels) and molecular (<jats:italic toggle=\"yes\">c-jun<\/jats:italic> and <jats:italic toggle=\"yes\">c-fos<\/jats:italic> messenger RNA [mRNA] levels and activator protein 1 [AP-1] DNA binding activity) parameters were measured, as well as the consequent effects on \u03b3-GCS levels and activity. All compounds produced GSH depletion, but only the higher doses of APAP and CCl<jats:sub>4<\/jats:sub> caused liver damage. DEM, APAP, and CCl<jats:sub>4<\/jats:sub> increased <jats:italic toggle=\"yes\">c-jun<\/jats:italic> and <jats:italic toggle=\"yes\">c-fos<\/jats:italic> mRNA levels, together with an increase in AP-1 binding; BSO failed to induce AP-1 despite an increase in <jats:italic toggle=\"yes\">c-fos<\/jats:italic>. Interestingly, the effects on \u03b3-GCS varied markedly according to the compound: BSO and DEM increased \u03b3-GCS enzyme activity, although only DEM, but not BSO, resulted in an increase in \u03b3-GCS<jats:sub>h<\/jats:sub> mRNA and protein. In contrast, APAP and CCl<jats:sub>4<\/jats:sub> both increased \u03b3-GCS<jats:sub>h<\/jats:sub> mRNA and protein; however, there was a marked dose-dependent decrease in \u03b3-GCS activity. These data indicate that the effect of chemical stress on the liver is compound specific and is not merely dependent on depletion of GSH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2000.9602","type":"journal-article","created":{"date-parts":[[2004,3,19]],"date-time":"2004-03-19T22:03:01Z","timestamp":1079733781000},"page":"321-333","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Hepatocellular response to chemical stress in CD-1 mice: Induction of early genes and \u03b3-glutamylcysteine synthetase"],"prefix":"10.1097","volume":"32","author":[{"given":"Neil R.","family":"Kitteringham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Powell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri 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