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

Merrie Mosedale, Yunjung Kim, William J. Brock, Sharin E. Roth, Tim Wiltshire, J. Scott Eaddy, Gregory R. Keele, Robert W. Corty, Yuying Xie, William Valdar, Paul B. Watkins

Research output: Contribution to journalArticle

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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 tolvaptaninduced 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.

LanguageEnglish (US)
Article numberkfw269
Pages438-454
Number of pages17
JournalToxicological Sciences
Volume156
Issue number2
DOIs
StatePublished - Apr 1 2017

Fingerprint

Liver
Chemical and Drug Induced Liver Injury
Wounds and Injuries
Secretory Leukocyte Peptidase Inhibitor
Autosomal Dominant Polycystic Kidney
Oxidative stress
Pharmaceutical Preparations
Genes
Bile Acids and Salts
Alanine Transaminase
Oxidative Stress
Homeostasis
Biomarkers
Interferon Regulatory Factor-3
Mitochondrial Dynamics
Plasmas
Epoxide Hydrolases
tolvaptan
Innate Immunity
Population

Keywords

  • Collaborative cross
  • Drug-induced liver injury
  • Precision medicine
  • Tolvaptan
  • Toxicogenomics

ASJC Scopus subject areas

  • Toxicology

Cite this

Candidate risk factors and mechanisms for tolvaptan-induced liver injury are identified using a collaborative cross approach. / Mosedale, Merrie; Kim, Yunjung; Brock, William J.; Roth, Sharin E.; Wiltshire, Tim; Eaddy, J. Scott; Keele, Gregory R.; Corty, Robert W.; Xie, Yuying; Valdar, William; Watkins, Paul B.

In: Toxicological Sciences, Vol. 156, No. 2, kfw269, 01.04.2017, p. 438-454.

Research output: Contribution to journalArticle

Mosedale, Merrie ; Kim, Yunjung ; Brock, William J. ; Roth, Sharin E. ; Wiltshire, Tim ; Eaddy, J. Scott ; Keele, Gregory R. ; Corty, Robert W. ; Xie, Yuying ; Valdar, William ; Watkins, Paul B./ Candidate risk factors and mechanisms for tolvaptan-induced liver injury are identified using a collaborative cross approach. In: Toxicological Sciences. 2017 ; Vol. 156, No. 2. pp. 438-454
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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 tolvaptaninduced 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.",
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AU - Kim,Yunjung

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AU - Wiltshire,Tim

AU - Eaddy,J. Scott

AU - Keele,Gregory R.

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AU - Xie,Yuying

AU - Valdar,William

AU - Watkins,Paul B.

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AB - 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 tolvaptaninduced 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.

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