title: Editor's Highlight: Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach.
abstract: 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.
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709.|Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599.
authors.forename: Merrie
authors.initials: M
authors.lastname: Mosedale
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709.|Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Yunjung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850.|Brock Scientific Consulting, Montgomery Village, Maryland 20886.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brock
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850.
authors.forename: Sharin E
authors.initials: SE
authors.lastname: Roth
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599.|Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709.|Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Eaddy
authors.affiliation: Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Keele
authors.affiliation: Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Corty
authors.affiliation: Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.|Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599.
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.affiliation: Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709.|Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D008111:Liver Function Tests; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D012307:Risk Factors; D013045:Species Specificity; D000077602:Tolvaptan; D043922:Toxicogenetics; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D015415:Biomarkers; D000077602:Tolvaptan
keywords: Collaborative Cross; drug-induced liver injury; precision medicine; tolvaptan; toxicogenomics.