{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T19:53:16Z","timestamp":1783626796442,"version":"3.55.0"},"reference-count":45,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"DNTP\/NIEHS intramural program","award":["ES103319-06 (2021) and ES102505-14 (2021)"],"award-info":[{"award-number":["ES103319-06 (2021) and ES102505-14 (2021)"]}]},{"DOI":"10.13039\/501100001691","name":"JSPS (Japan Society for the Promotion of Science) Fund for the Promotion of Joint International Research","doi-asserted-by":"publisher","award":["Grant no. 17KK0158"],"award-info":[{"award-number":["Grant no. 17KK0158"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and its influence on drug-induced liver injury (DILI) is not fully understood. We investigated whether NAFLD can influence acetaminophen (APAP [N-acetyl-p-aminophenol])-induced hepatotoxicity in a diet-induced obese (DIO) mouse model of NAFLD. The male C57BL\/6NTac DIO mice, fed a high-fat diet for more than 12 weeks, developed obesity, hyperinsulinemia, impaired glucose tolerance, and hepatomegaly with hepatic steatosis, similar to human NAFLD. In the acute toxicity study after a single dose of APAP (150 mg\/kg), compared with control lean mice, the DIO mice had decreased serum transaminase levels and less severe hepatocellular injury. The DIO mice also had altered expression of genes related to APAP metabolism. Chronic APAP exposure for 26 weeks did not predispose the DIO mice with NAFLD to more severe hepatotoxicity compared with the lean mice. These results suggested that the C57BL\/6NTac DIO mouse model appears to be more tolerant to APAP-induced hepatotoxicity than lean mice, potentially related to altered xenobiotic metabolizing capacity in the fatty liver. Further mechanistic studies with APAP and other drugs in NAFLD animal models are necessary to investigate the mechanism of altered susceptibility to intrinsic DILI in some human NAFLD patients.<\/jats:p>","DOI":"10.1177\/01926233231171101","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T23:37:13Z","timestamp":1683675433000},"page":"112-125","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Absence of Increased Susceptibility to Acetaminophen-Induced Liver Injury in a Diet-Induced NAFLD Mouse Model"],"prefix":"10.1177","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-6050","authenticated-orcid":false,"given":"Takeshi","family":"Izawa","sequence":"first","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"},{"name":"Osaka Metropolitan University, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Travlos","sequence":"additional","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo A.","family":"Cortes","sequence":"additional","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"},{"name":"Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha P.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Sills","sequence":"additional","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0963-9073","authenticated-orcid":false,"given":"Arun R.","family":"Pandiri","sequence":"additional","affiliation":[{"name":"Comparative and Molecular Pathogenesis Branch, Division of Translational Toxicology, National Institute of Environmental Health Services, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.014"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0144-8"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.03.039"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.11.312"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.11.008"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29367"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.10.031"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0105-0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.02.014"},{"key":"e_1_3_3_11_2","first-page":"212","article-title":"Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity","volume":"3","author":"Massart J","year":"2017","unstructured":"Massart J, Begriche K, Moreau C, Fromenty B. 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NTP technical report on the toxicology and carcinogenesis studies of acetaminophen (CAS no. 103-90-2) in F344\/N rats and B6C3Fl mice (feed studies). U.S. Department of Health and Human Services Public Health Service National Institute of Health. Published 1993. Accessed April 10 2023. https:\/\/agris.fao.org\/agris-search\/search.do?recordID=US201300226783."},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.4103\/0976-0105.177703"},{"key":"e_1_3_3_28_2","unstructured":"Food and Drug Administration. FDA Drug Safety Communication: prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. U.S. Department of Health and Human Services Center for Biologics Evaluation and Research Pharmacology and Toxicology. Date unknown. 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