{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T22:23:15Z","timestamp":1785709395037,"version":"3.56.0"},"reference-count":50,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[1994,11,1]],"date-time":"1994-11-01T00:00:00Z","timestamp":783648000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[1994,11]]},"abstract":"<jats:p>\n                    The early cellular events in liver carcinogenesis were studied in Fischer-344 male rats that either were fed 200 ppm 2-acetylaminofluorene (AAF) for up to 10 wk or were fed the carcinogen for 8 wk followed by maintenance for an additional 24 wk. By 1 wk of exposure, AAF caused a reduction in the number of glutamine synthetase (GS)-positive centrilobular hepatocytes, an increase in DNA synthesizing hepatocytes in the central areas of the hepatic lobules, and a shift from multinucleated to mononucleated hepatocytes, although overt hepatocellular necrosis was not evident. By 3 wk, altered hepatocellular foci characterized by deficiencies in iron storage (IS\n                    <jats:sup>-<\/jats:sup>\n                    ) and collagen production and by expression of gamma-glutamyl transferase (GGT\n                    <jats:sup>+<\/jats:sup>\n                    ) and placental-type glutathione transferase (PGT\n                    <jats:sup>+<\/jats:sup>\n                    ) activity appeared. Single PGT+ cells were also found. During continued exposure, foci increased in number, size, and total area with the increases escalating between 8 and 10 wk of exposure. Cessation of AAF exposure at 8 wk resulted in a slight decrease in the number of foci after a further 6 wk of maintenance, but with continued maintenance for another 6 and 12 wk, the number again increased. IS\n                    <jats:sup>-<\/jats:sup>\n                    characterized the majority of foci during carcinogen administration, whereas after cessation of exposure, GGT+ and PGT+ foci predominated. None of the foci were positive for GS. After AAF exposure for 10 wk, a few neoplasms developed and greater numbers occurred after maintenance for a further 24 wk of rats exposed for 8 wk. We conclude the following: (a) the low dose of AAF caused subtle alterations in function and proliferation of normal hepatocytes and converted hepatocytes into focus cells; (b) reduction of the GS+ area is a sensitive indicator of cytotoxicity of AAF; (c) the development of some foci at an early stage depends on a promoting action of AAF, which ceased when the carcinogen was withdrawn, allowing some foci to undergo reversion; (d) a strong linkage exists in expression of IS-, GGT+, and PGT+ in foci; (e) the carcinogenic process accelerates in the absence of any indication of increased cytotoxicity by AAF; and (f) under the conditions of this study, no GS+ foci, adenomas, and carcinomas were found, indicating that no carcinogen-induced expression of GS occurred in these lesions and that GS expression is not linked to other phenotypic abnormalities.\n                  <\/jats:p>","DOI":"10.1177\/019262339402200606","type":"journal-article","created":{"date-parts":[[2009,4,1]],"date-time":"2009-04-01T19:16:47Z","timestamp":1238613407000},"page":"620-632","source":"Crossref","is-referenced-by-count":11,"title":["Sequential Functional and Morphological Alterations During Hepatocarcinogenesis Induced in Rats by Feeding of a Low Dose of 2-Acetylaminofluorene"],"prefix":"10.1177","volume":"22","author":[{"given":"Frej","family":"Stenb\u00e4ck","sequence":"first","affiliation":[{"name":"'Department of Pathology, University of Oulu, Kajaanintie 52 D, SF 90220, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Gebhardt","sequence":"additional","affiliation":[{"name":"Physiologisch-chemisches Institut der Universit\u00e4t, Hoppe-Seyler-strasse 4, D-7400 Tubingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein","family":"Sirma","sequence":"additional","affiliation":[{"name":"Physiologisch-chemisches Institut der Universit\u00e4t, Hoppe-Seyler-strasse 4, D-7400 Tubingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Garbay","sequence":"additional","affiliation":[{"name":"Centre de Reserches Clin Midi Sanofi, rue du Pr. J. Blayac, 34082 Montpellier Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Williams","sequence":"additional","affiliation":[{"name":"American Health Foundation, 1 Dana Road, Valhalla, New York 10595, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[1994,11,1]]},"reference":[{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/5.4.453"},{"key":"atypb2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02889898"},{"key":"atypb3","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4613-0957-4_12"},{"key":"atypb4","first-page":"441","volume":"116","author":"Columbano A.","year":"1984","journal-title":"Am. J. 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