Editor's Highlight: Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach.

Autor:	Mosedale M; 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., Kim Y; 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., Brock WJ; Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850.; Brock Scientific Consulting, Montgomery Village, Maryland 20886., Roth SE; Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland 20850., Wiltshire T; 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., Eaddy JS; 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., Keele GR; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599., Corty RW; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599., Xie Y; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599., Valdar W; Department of Genetics, UNC School of Medicine, Chapel Hill, North Carolina 27599.; Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599., Watkins PB; 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.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2017 Apr 01; Vol. 156 (2), pp. 438-454.
DOI:	10.1093/toxsci/kfw269
Abstrakt:	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. (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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