{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:55:53Z","timestamp":1791276953017,"version":"4.1.0"},"reference-count":47,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2003,7,1]],"date-time":"2003-07-01T00:00:00Z","timestamp":1057017600000},"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":["Int J Toxicol"],"published-print":{"date-parts":[[2003,7]]},"abstract":"<jats:p>\n                    Metolachlor (2-chloro- N-(2-ethyl-6-methylphenyl)- N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S. pesticide registration include increased liver weight and hepatocarcinogenicity associated with eosinophilic foci. These properties, plus nongenotoxicity, are also characteristic of the prototypical rat liver tumor promoter, phenobarbital. Phenobarbital induces hepatic cytochrome P450s CYP2B1\/2 and CYP3A1\/2 and thyroxine (T\n                    <jats:sub>4<\/jats:sub>\n                    )-UDP-glucuronosyltransferase (T\n                    <jats:sub>4<\/jats:sub>\n                    -UGT), which enhances thyroxine clearance and thus indirectly increases thyroid gland activity. Because other chloroacetanilide herbicides are known to similarly affect rat thyroid gland, this study tested the hypothesis that metolachlor would have these additional phenobarbital-like effects on liver, especially that of T\n                    <jats:sub>4<\/jats:sub>\n                    -UGT induction with consequential stimulation of thyroid gland. Effects of metolachlor, fed to male Sprague-Dawley rats for 14 days at the carcinogenic dose of 3000 ppm, were compared to those of equimolar phenobarbital. Liver microsomal CYP2B1\/2 and CYP3A1\/2 were probed by immunoblotting and T\n                    <jats:sub>4<\/jats:sub>\n                    -UGT was measured enzymat-ically. Serum T\n                    <jats:sub>4<\/jats:sub>\n                    , triiodothyronine (T\n                    <jats:sub>3<\/jats:sub>\n                    ), and thyroid-stimulating hormone (TSH) and thyroid follicular epithelial cell morphology and proliferation were used to assess thyroid gland activity. Metolachlor induced CYP2B1\/2 and CYP3A1\/2 proteins, but unlike phenobarbital, did not affect T\n                    <jats:sub>4<\/jats:sub>\n                    -UGT activity. In agreement, serum T\n                    <jats:sub>4<\/jats:sub>\n                    , T\n                    <jats:sub>3<\/jats:sub>\n                    , or TSH were unaffected by metolachlor. Also, no significant effects of metolachlor on thyroid gland morphology or follicular epithelial cell height or proliferation were observed. These data demonstrate that metolachlor is an inducer of hepatic CYP2B1\/2 activity. But unlike the prototypical CYP2B1\/2 inducer phenobarbital, metolachlor does not cause an increase in T\n                    <jats:sub>4<\/jats:sub>\n                    -glucuronidation and thyroid gland activation.\n                  <\/jats:p>","DOI":"10.1080\/10915810305121","type":"journal-article","created":{"date-parts":[[2003,9,18]],"date-time":"2003-09-18T18:40:18Z","timestamp":1063910418000},"page":"287-295","source":"Crossref","is-referenced-by-count":20,"title":["The Herbicide Metolachlor Induces Liver Cytochrome P450s 2B1\/2 and 3A1\/2, but Not Thyroxine-Uridine Dinucleotide Phosphate Glucuronosyltransferase and Associated Thyroid Gland Activity"],"prefix":"10.1177","volume":"22","author":[{"given":"Shana R.","family":"Dalton","sequence":"first","affiliation":[{"name":"Department of Toxicology, North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T.","family":"Miller","sequence":"additional","affiliation":[{"name":"Glaxo Smith Kline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon A.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Toxicology, University of Louisiana at Monroe, Monroe, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2003,7,1]]},"reference":[{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.2134\/jeq2001.303831x"},{"key":"atypb2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(92)90006-E"},{"key":"atypb3","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1994.1174"},{"key":"atypb4","doi-asserted-by":"publisher","DOI":"10.1210\/endo-128-2-741"},{"key":"atypb5","first-page":"401","volume-title":"Comprehensive toxicology","author":"Burchell, B.","year":"1997"},{"key":"atypb6","unstructured":"Burin, G. J. 1982. Subject: Review of data for metolachlor, accession nos.: 345957\u201361, letter through Orville E. Paynter, Toxicology Branch, Hazard Evaluation Division (HED), U.S. Environmental Protection Agency to Richard Mountfort, U.S. Environmental Protection Agency, HED document no. 001374."},{"key":"atypb7","unstructured":"Burin, G. J. 1983. Subject: Review of chronic rat study of metolachlor, accession nos.: 250369\u201375, letter through William L. Burnam, Toxicology Branch, Hazard Evaluation Division (HED), U.S. Environmental Protection Agency to R. Mountfort and J. Mc Cann, U.S. Environmental Protection Agency, HED document no. 003435."},{"key":"atypb8","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(94)90363-8"},{"key":"atypb9","doi-asserted-by":"publisher","DOI":"10.1177\/019262339702500109"},{"key":"atypb10","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/68.2.372"},{"key":"atypb11","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2000.8935"},{"key":"atypb12","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5742(99)00019-8"},{"key":"atypb13","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.99107407"},{"key":"atypb14","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007619919336"},{"key":"atypb15","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.93101s5207"},{"key":"atypb16","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(94)90303-4"},{"key":"atypb17","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012426260-7.50072-0"},{"key":"atypb18","doi-asserted-by":"publisher","DOI":"10.1081\/DCT-100108470"},{"key":"atypb19","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1999.8752"},{"key":"atypb20","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/55.1.78"},{"key":"atypb21","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/50.1.45"},{"key":"atypb22","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/49.2.263"},{"key":"atypb23","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.98106437"},{"key":"atypb24","doi-asserted-by":"publisher","DOI":"10.1007\/BF01974069"},{"key":"atypb25","doi-asserted-by":"publisher","DOI":"10.1080\/019262301301418838"},{"key":"atypb26","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(01)00843-7"},{"key":"atypb27","doi-asserted-by":"publisher","DOI":"10.2134\/jeq2002.1636"},{"key":"atypb28","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.2570050108"},{"key":"atypb29","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/60.1.63"},{"key":"atypb30","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(89)90004-5"},{"key":"atypb31","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(88)90267-0"},{"key":"atypb32","volume-title":"Guide for the care and use of laboratory animals.","author":"National Research Council.","year":"1996"},{"key":"atypb33","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/69.1.79"},{"key":"atypb34","unstructured":"Piegorsch, W. W., and A. J. Bailer. 1997. Statistics for environmental biology and toxicology, 128, 184\u2013194. London: Chapman & Hall."},{"key":"atypb35","doi-asserted-by":"publisher","DOI":"10.1177\/0192623389017004102"},{"key":"atypb36","first-page":"503","volume":"51","author":"Saeed, A.","year":"1997","journal-title":"J. Toxicol. Environ. Health"},{"key":"atypb37","volume-title":"SAS\/STAT user's guide","author":"SAS Institute Inc.","year":"1990","edition":"4"},{"key":"atypb38","volume-title":"The laboratory rat.","author":"Sharp, P. E.","year":"1998"},{"key":"atypb39","volume-title":"Principles and procedures of statistics.","author":"Steel, R. G. D.","year":"1960"},{"key":"atypb40","unstructured":"U.S. Department of Agriculture, National Agricultural Statistics Service and Economic Research Service. 2002.\n                      Agricultural chemical usage. 2001 field crops summary.\n                      Available (Since 10 December 2002) at: http:\/\/usda.mannlib.cornell.edu\/reports\/nassr\/other\/pcu-bb\/agcs0502.pdf"},{"key":"atypb41","first-page":"49480","volume":"52","author":"U.S. Environmental Protection Agency.","year":"1987","journal-title":"Federal Register"},{"key":"atypb42","unstructured":"U.S. Environmental Protection Agency. 1995. Reregistration Eligibility Decision (RED). Metolachlor. Office of Pesticide Programs. EPA-738-R-95\u2013006, April 1995."},{"key":"atypb43","unstructured":"U.S. Environmental Protection Agency. 1998. Reregistration Eligibility Decision (RED). Alachlor. Office of Pesticide Programs. 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