U.S. flag

An official website of the United States government

Dot gov

The .gov means it's official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Zileuton Liver Toxicity Study in DO Mice

Dahea You, Lascelles E. Lyn-Cook Jr., Daniel M. Gatti, Natalie Bell,, Philip R. Mayeux, Laura P. James, William B. Mattes, Alison H. Harrill.
DOI: https://doi.org/10.22427/NTP-DATA-002-00076-0001-0000-6

Publication

Abstract

Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. 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 i.g. daily for seven days. Serum liver enzymes were significantly elevated in the zileuton group, with marked interindividual variability in response. Zileuton treatment-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase (iNOS) 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 FXR signaling may contribute to zileuton-induced liver injury. Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of zileuton-induced liver injury which may lead to targeted therapeutic interventions.

Data

RNA Sequence Data

A full dataset for the clinical measurements of all the samples in the study - Processed count data (raw count and normalized count) for RNA-seq