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Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa037","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T20:25:15Z","timestamp":1583958315000},"page":"220-235","source":"Crossref","is-referenced-by-count":16,"title":["Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice"],"prefix":"10.1093","volume":"175","author":[{"given":"Dahea","family":"You","sequence":"first","affiliation":[{"name":"Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Lascelles E","family":"Lyn-Cook","sequence":"first","affiliation":[{"name":"Graduate Program in Interdisciplinary Biomedical Sciences, The University of Arkansas for Medical Sciences and Arkansas Children\u2019s Research Institute, Little Rock, Arkansas 72205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M","family":"Gatti","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Bell","sequence":"first","affiliation":[{"name":"Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709"},{"name":"East Carolina University, Greenville, North Carolina 27858"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip R","family":"Mayeux","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P","family":"James","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The University of Arkansas for Medical Sciences and Arkansas Children\u2019s Research Institute, Little Rock, Arkansas 27705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B","family":"Mattes","sequence":"first","affiliation":[{"name":"Division of Systems Biology, The National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary J","family":"Larson","sequence":"first","affiliation":[{"name":"Social & Scientific Systems, Inc., Durham, North Carolina 27703"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5544-1338","authenticated-orcid":false,"given":"Alison H","family":"Harrill","sequence":"first","affiliation":[{"name":"Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709"},{"name":"Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences and Arkansas Children\u2019s Research Institute, Little Rock, Arkansas 72205"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,14]]},"reference":[{"key":"2020052717295199400_kfaa037-B1","doi-asserted-by":"crossref","first-page":"28857","DOI":"10.1074\/jbc.M011610200","article-title":"Human bile salt export pump promoter is transactivated by the farnesoid X receptor\/bile acid receptor","volume":"276","author":"Ananthanarayanan","year":"2001","journal-title":"J. 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