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Identification of Pharmacogenetic Risk Factors for Zileuton‐Induced Liver Injury Using Diversity Outbred Mice
Author(s) -
Harrill Alison,
Gatti Daniel M,
Luo Shaoke,
Lyncook Lascelles,
Churchill Gary
Publication year - 2017
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.31.1_supplement.1066.4
Subject(s) - zileuton , steatosis , medicine , population , liver injury , leukotriene , gastroenterology , pharmacology , immunology , biology , arachidonate 5 lipoxygenase , asthma , biochemistry , environmental health , arachidonic acid , enzyme
Zileuton is an orally active inhibitor of leukotriene synthesis that is currently used for the maintenance treatment of asthma, although there has been interest in expanding its indications to other inflammatory diseases involving leukotrienes, such as rheumatoid arthritis and inflammatory bowel disease. A limitation for expanding clinical usage is an association with rare (idiosyncratic), but serious liver injury. In this study, we hypothesized that genetic sequence variants could be identified that influence risk of zileuton‐induced hepatotoxicity. Diversity Outbred (DO) mice were used as a surrogate for the human population because they harbor a high degree of genetic diversity and this diversity is well‐randomized throughout the genome, providing an ideal platform for complex trait analysis. In this study, female DO mice were administered zileuton (300 mg/kg, N=400) or vehicle (N=50) and dosed daily for seven days (i.g.). Serum alanine aminotransferase (ALT) was significantly elevated in the zileuton group, with significant interindividual variability in response (mean ± SD and range ‐ vehicle: 38 ± 53, 16–71 U/L; zileuton: 48 ± 42, 14–481 U/L; P<0.05). Zileuton treatment‐induced histopathological findings included microvesicular steatosis (37.5%, 150/400 mice), increased mitosis (3.5%, 14/400 mice), and focal and multifocal hepatocellular necrosis (2%, 8/400 mice). Quantitative trait locus mapping of the terminal ALT level revealed a significantly associated gene region on chromosome 3 (log of odds (LOD)=6), with smaller suggestive peaks on chromosomes 5, 11, 13, 16, and 18, suggesting multiple genetic contributors to the toxicity response. Within the Chr 3 support interval lies several promising candidate genes, including: 1) Tpmt (thiopurine methyltransferase) for which genetic variants have been used to select dosages of several drugs known to cause adverse reactions in the clinic, and 2) Ltc4s (leukotriene C4 synthase), for which variant rs730012 is used to predict an increase in asthma exacerbations for patients administered the leukotriene receptor inhibitor drug montelukast. Taken together, our data provide a starting point for identifying the underlying genetic sequence variants that contribute to zileuton‐induced liver injury in susceptible patients. Follow up studies are ongoing to confirm a functional role and human relevance of the candidate pharmacogenetic risk alleles identified in the present study. Support or Funding Information This work was supported by the Food and Drug Administration [HHSF223201400183C], Burroughs Wellcome Fund Innovation in Regulatory Sciences Award, Arkansas Biosciences Institute, NIH [Translational Research Institute grant UL1TR000039 and T32 GM106999].