{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:07:19Z","timestamp":1777914439366,"version":"3.51.4"},"reference-count":16,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[1991,2,1]],"date-time":"1991-02-01T00:00:00Z","timestamp":665366400000},"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":[[1991,2]]},"abstract":"<jats:p>This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK &amp; F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,1-b)thiazole], an inhibitor of both the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The induction characteristics of SK &amp; F 86002 were compared to those of the classical inducer, phenobarbital, and morphological features of both SK &amp; F 86002 and phenobarbital induced hepatocellular hypertrophy were quantitated.<\/jats:p>\n                  <jats:p>\n                    Rats were administered either SK &amp; F 86002 (6, 18, or 60 mg\/kg\/day, po) or phenobarbital (8, 24, 80 mg\/kg\/day, ip) for 3 or 14 consecutive days. Liver to body weight ratio, total hepatic microsomal protein and cytochrome P-450 content, ethoxycoumarin-O-deethylase (ECOD) and leukotriene B\n                    <jats:sub>4<\/jats:sub>\n                    (LTB\n                    <jats:sub>4<\/jats:sub>\n                    ) \u03c9- and \u03c9-1 hydroxylase were measured. Ultrastructural morphometry of the liver from control, and high dose SK &amp; F 86002 (60 mg\/kg\/day) and phenobarbital (80 mg\/kg\/day) treated rats was completed.\n                  <\/jats:p>\n                  <jats:p>\n                    On day 3, phenobarbital increased liver to body weight ratio but only at the 80 mg\/kg\/day dosage; microsomal protein content was unchanged. ECOD activity increased in a dose-dependent fashion. LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9-and \u03c9-1 hydroxylase activities were unaffected. Administration of SK &amp; F 86002 for 3 days increased the liver to body weight ratio at both the 18 and 60 mg\/kg\/day dosage; microsomal protein content was unchanged. ECOD activity was significantly increased by the 60 mg\/kg\/day dosage. LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9-, but not \u03c9-1 hydroxylase activity was increased by both the 18 and 60 mg\/kg\/day dosages of SK &amp; F 86002.\n                  <\/jats:p>\n                  <jats:p>\n                    On day 14, phenobarbital increased the liver to body weight ratio and microsomal protein content but again only at the 80 mg\/kg\/day dosage. Cytochrome P-450 content was increased by all dosages. A dose-dependent increase in ECOD activity was observed but there was no change in LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9- or \u03c9-1 hydroxylase activity on day 14.\n                  <\/jats:p>\n                  <jats:p>\n                    Administration of SK &amp; F 86002 (60 mg\/kg\/day) for 14 days increased the liver to body weight ratio. Microsomal protein content was unaffected but cytochrome P-450 content and ECOD activity were increased at the 60 mg\/kg\/day dosage. Similar to the day 3 observation, LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9-hydroxylase activity was increased by the 18 and 60 mg\/kg\/day dosages of SK &amp; F 86002; LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9-1 hydroxylase was unchanged.\n                  <\/jats:p>\n                  <jats:p>Quantitative evaluation of hepatocyte ultrastructural characteristics indicated that the volume percent (Vv) of smooth endoplasmic reticulum (SER) was increased but that cytosol and mitochondrial Vv significantly decreased after 3 days of phenobarbital treatment. Three days of treatment with SK &amp; F 86002 also increased the Vv of SER; Vv of cytosol was decreased but the mitochondrial Vv was unchanged from control values.<\/jats:p>\n                  <jats:p>SER Vv was increased after 14 days of phenobarbital treatment but cytosol Vv was not significantly affected. Similar to the 3 day results, mitochondrial Vv decreased in phenobarbital treated rats. SK &amp; F 86002 treatment for 14 days increased the SER Vv and decreased cytosol Vv. Mitochondrial Vv was unaffected.<\/jats:p>\n                  <jats:p>\n                    These studies confirm that SK &amp; F 86002 is an inducer of the cytochrome P-450 mixed function oxidase system but with an induction profile somewhat different from phenobarbital. The principal difference being that SK &amp; F 86002 was a potent inducer of LTB\n                    <jats:sub>4<\/jats:sub>\n                    \u03c9-hydroxylase, a feature not associated with phenobarbital induction. SK &amp; F 86002 and phenobarbital share similar ultrastructural hepatic changes both increasing the Vv of hepatocyte SER. However, a reduction in the Vv of mitochondria within the hepatocyte was only associated with phenobarbital treatment; this occurred on both days 3 and 14. These observations suggest that both biochemical and morphological differences are present in hepatocytes from rats treated with differing P-450 inducers.\n                  <\/jats:p>","DOI":"10.1177\/019262339101900205","type":"journal-article","created":{"date-parts":[[2009,9,14]],"date-time":"2009-09-14T21:30:11Z","timestamp":1252963811000},"page":"115-122","source":"Crossref","is-referenced-by-count":10,"title":["Comparative Biochemical and Morphometric Changes Associated with Induction of the Hepatic Mixed Function Oxidase System in the Rat"],"prefix":"10.1177","volume":"19","author":[{"given":"Monica O.","family":"Howard","sequence":"first","affiliation":[{"name":"Departments of Experimental Pathology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lester W.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Departments of Experimental Pathology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F.","family":"Newton","sequence":"additional","affiliation":[{"name":"Drug Metabolism"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Charles W.","family":"Qualls","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma 74078"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee Ann P.","family":"Yodis","sequence":"additional","affiliation":[{"name":"Drug Metabolism"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John R.","family":"Ventre","sequence":"additional","affiliation":[{"name":"Scientific Statistical Services, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, Swedeland, Pennsylvania 19479"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[1991,2,1]]},"reference":[{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(76)90132-0"},{"key":"atypb2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)57021-6"},{"key":"atypb3","first-page":"369","volume":"15","author":"Howard-Martin MO","year":"1987","journal-title":"Toxicol. Pathol."},{"key":"atypb4","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.2460\/ajvr.1980.41.12.1966","volume":"41","author":"Kocan KM","year":"1980","journal-title":"Am. J. Vet. Res."},{"key":"atypb5","first-page":"164","volume":"5","author":"Lee NH","year":"1985","journal-title":"Toxicologist"},{"key":"atypb6","first-page":"29","volume-title":"Analysis of Messy Data","author":"Milliken GA","year":"1984"},{"key":"atypb7","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(85)90108-1"},{"key":"atypb8","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)82244-3"},{"key":"atypb9","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)75676-2"},{"key":"atypb10","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(79)90368-X"},{"key":"atypb11","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.42.1.92"},{"key":"atypb12","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0090-9556(25)05632-6","volume":"1","author":"Valerino DM","year":"1973","journal-title":"Drug Met. 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