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Idiosyncratic Drug‐Induced Liver Injury Potential of Zileuton is Detected in Diversity Outbred Mice
Author(s) -
Harrill Alison,
Lyncook Lascelles,
Gatti Daniel,
Luo Shaoke,
Churchill Gary
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.937.3
Subject(s) - zileuton , medicine , liver injury , pharmacology , drug , arachidonate 5 lipoxygenase , gastroenterology , biology , biochemistry , arachidonic acid , enzyme
Zileuton is an orally active inhibitor of 5‐lipoxygenase used clinically for maintenance treatment of asthma. While also a promising candidate for other inflammatory diseases involving leukotrienes, such as rheumatoid arthritis and inflammatory bowel disease, enthusiasm for expanding its indications is tempered by rare instances of associated drug‐induced liver injury (DILI). Mechanistic understanding of zileuton DILI is hampered by the rarity of the cases and lack of an animal model. A promising model for rare liver injury is the Diversity Outbred (DO) mouse population, which contains genetic variation that is similar to that found in humans. We hypothesized that zileuton DILI could be mediated by rare genetic alleles that are harbored by sensitive patients and thus used the DO mice as a surrogate model for clinical populations. Female DO mice (N=50/group) were orally administered zileuton (300 mg/kg) or vehicle for seven days. Significant elevations in alanine aminotransferase (ALT) were elicited by zileuton ( P <0.05), but not the vehicle. Sensitive and resistant individuals were observed in the zileuton group with ALT elevations ranging from 0.2‐13.6 fold over baseline. Group mean±SEM for the zileuton and vehicle groups were 123.8±10.0 U/L and 32.39±5.4 U/L, respectively. MiR‐122 elevations in plasma confirmed the liver origin of the ALT release ( P <0.05). The data provide an important first step to identifying the DO as an animal model for idiosyncratic DILI due to zileuton. This work is supported by the Burroughs Wellcome Fund, Arkansas Biosciences Institute, NIH [TRI UL1TR000039 and T32 GM106999].