Data from: Candidate risk factors and mechanisms for tolvaptan-induced liver injury are identified using a collaborative cross approach

Clinical trials of tolvaptan showed it to be a promising candidate for the
treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also
revealed potential for idiosyncratic drug-induced liver injury (DILI) in
this patient population. To identify risk factors and mechanisms
underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically
diverse Collaborative Cross (CC) mouse population were treated with a
single oral dose of either tolvaptan or vehicle. Significant elevations in
plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated
animals in 3 of the 45 strains. Genetic mapping coupled with
transcriptomic analysis in the liver was used to identify several
candidate susceptibility genes including epoxide hydrolase 2, interferon
regulatory factor 3, and mitochondrial fission factor. Gene pathway
analysis revealed that oxidative stress and immune response pathways were
activated in response to tolvaptan treatment across all strains, but genes
involved in regulation of bile acid homeostasis were most associated with
tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase
inhibitor (Slpi) mRNA was also induced in the susceptible strains and was
associated with increased plasma levels of Slpi protein, suggesting a
potential serum marker for DILI susceptibility. In summary, tolvaptan
induced signs of oxidative stress, mitochondrial dysfunction, and innate
immune response in all strains, but variation in bile acid homeostasis was
most associated with susceptibility to the liver response. This CC study
has indicated potential mechanisms underlying tolvaptan DILI and
biomarkers of susceptibility that may be useful in managing the risk of
DILI in ADPKD patients.