Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing
- Publication Date
- April 15, 2014
- Journal
- PLOS Medicine
- Authors
- Dan Xu, Toshi Nishimura, Sachiko Nishimura, Haili Zhang, et al
- Volume
- 11
- Issue
- 4
- Pages
- e1001628
- DOI
- https://dx.plos.org/10.1371/journal.pmed.1001628
- Publisher URL
- http://journals.plos.org/plosmedicine/article?id=10.1371%2Fjournal.pmed.1001628
- PubMed
- http://www.ncbi.nlm.nih.gov/pubmed/24736310
- PubMed Central
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988005
- Europe PMC
- http://europepmc.org/abstract/MED/24736310
- Web of Science
- 000335465800014
- Scopus
- 84900460907
- Mendeley
- http://www.mendeley.com/research/fialuridine-induces-acute-liver-failure-chimeric-tknog-mice-model-detecting-hepatic-drug-toxicity-pr
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Mendeley | Further Information
{"title"=>"Fialuridine Induces Acute Liver Failure in Chimeric TK-NOG Mice: A Model for Detecting Hepatic Drug Toxicity Prior to Human Testing", "type"=>"journal", "authors"=>[{"first_name"=>"Dan", "last_name"=>"Xu", "scopus_author_id"=>"25229234200"}, {"first_name"=>"Toshi", "last_name"=>"Nishimura", "scopus_author_id"=>"56157450600"}, {"first_name"=>"Sachiko", "last_name"=>"Nishimura", "scopus_author_id"=>"56157953500"}, {"first_name"=>"Haili", "last_name"=>"Zhang", "scopus_author_id"=>"56158223600"}, {"first_name"=>"Ming", "last_name"=>"Zheng", "scopus_author_id"=>"19236458100"}, {"first_name"=>"Ying Ying", "last_name"=>"Guo", "scopus_author_id"=>"9737868700"}, {"first_name"=>"Marylin", "last_name"=>"Masek", "scopus_author_id"=>"57200908949"}, {"first_name"=>"Sara A.", "last_name"=>"Michie", "scopus_author_id"=>"7004779977"}, {"first_name"=>"Jeffrey", "last_name"=>"Glenn", "scopus_author_id"=>"7202479598"}, {"first_name"=>"Gary", "last_name"=>"Peltz", "scopus_author_id"=>"7005048967"}], "year"=>2014, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491676", "sgr"=>"84900460907", "doi"=>"10.1371/journal.pmed.1001628", "scopus"=>"2-s2.0-84900460907", "isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "pmid"=>"24736310", "pui"=>"373076982"}, "id"=>"f4b43c75-56d3-377a-9b80-85729fa1abf8", "abstract"=>"BACKGROUND Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. METHODS AND FINDINGS Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. CONCLUSIONS FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.", "link"=>"http://www.mendeley.com/research/fialuridine-induces-acute-liver-failure-chimeric-tknog-mice-model-detecting-hepatic-drug-toxicity-pr", "reader_count"=>48, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>6}, "reader_count_by_subject_area"=>{"Engineering"=>4, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>8, "Materials Science"=>3, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>7, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>3, "Psychology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>4}, "Materials Science"=>{"Materials Science"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"United States"=>1, "United Kingdom"=>1}, "group_count"=>7}CrossRef
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Scopus | Further Information
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- {"month"=>"10", "year"=>"2017", "pdf_views"=>"14", "xml_views"=>"1", "html_views"=>"95"}
- {"month"=>"11", "year"=>"2017", "pdf_views"=>"13", "xml_views"=>"1", "html_views"=>"106"}
- {"month"=>"12", "year"=>"2017", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"48"}
- {"month"=>"1", "year"=>"2018", "pdf_views"=>"24", "xml_views"=>"1", "html_views"=>"59"}
- {"month"=>"2", "year"=>"2018", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"37"}
- {"month"=>"3", "year"=>"2018", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"38"}
- {"month"=>"4", "year"=>"2018", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"30"}
- {"month"=>"5", "year"=>"2018", "pdf_views"=>"16", "xml_views"=>"1", "html_views"=>"31"}
- {"month"=>"6", "year"=>"2018", "pdf_views"=>"14", "xml_views"=>"4", "html_views"=>"15"}
- {"month"=>"7", "year"=>"2018", "pdf_views"=>"17", "xml_views"=>"5", "html_views"=>"21"}
- {"month"=>"8", "year"=>"2018", "pdf_views"=>"11", "xml_views"=>"1", "html_views"=>"16"}
- {"month"=>"9", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"1", "html_views"=>"21"}
- {"month"=>"10", "year"=>"2018", "pdf_views"=>"14", "xml_views"=>"1", "html_views"=>"24"}
- {"month"=>"11", "year"=>"2018", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"30"}
- {"month"=>"12", "year"=>"2018", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"33"}
- {"month"=>"1", "year"=>"2019", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"39"}
- {"month"=>"2", "year"=>"2019", "pdf_views"=>"16", "xml_views"=>"0", "html_views"=>"72"}
- {"month"=>"3", "year"=>"2019", "pdf_views"=>"12", "xml_views"=>"1", "html_views"=>"37"}
- {"month"=>"4", "year"=>"2019", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"31"}
- {"month"=>"5", "year"=>"2019", "pdf_views"=>"8", "xml_views"=>"1", "html_views"=>"32"}
- {"month"=>"6", "year"=>"2019", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"33"}
- {"month"=>"7", "year"=>"2019", "pdf_views"=>"25", "xml_views"=>"0", "html_views"=>"25"}
- {"month"=>"8", "year"=>"2019", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"17"}
- {"month"=>"9", "year"=>"2019", "pdf_views"=>"27", "xml_views"=>"0", "html_views"=>"35"}
- {"month"=>"10", "year"=>"2019", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"28"}
- {"month"=>"11", "year"=>"2019", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"39"}
- {"month"=>"12", "year"=>"2019", "pdf_views"=>"1", "xml_views"=>"0", "html_views"=>"19"}
PMC Usage Stats | Further Information
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- {"unique-ip"=>"31", "full-text"=>"29", "pdf"=>"22", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"34", "cited-by"=>"0", "year"=>"2014", "month"=>"4"}
- {"unique-ip"=>"30", "full-text"=>"30", "pdf"=>"14", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"7"}
- {"unique-ip"=>"27", "full-text"=>"28", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"10", "cited-by"=>"0", "year"=>"2014", "month"=>"8"}
- {"unique-ip"=>"31", "full-text"=>"30", "pdf"=>"23", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"9"}
- {"unique-ip"=>"20", "full-text"=>"18", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2014", "month"=>"10"}
- {"unique-ip"=>"24", "full-text"=>"28", "pdf"=>"7", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"11"}
- {"unique-ip"=>"16", "full-text"=>"16", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
- {"unique-ip"=>"20", "full-text"=>"18", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"1"}
- {"unique-ip"=>"30", "full-text"=>"33", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2015", "month"=>"2"}
- {"unique-ip"=>"33", "full-text"=>"32", "pdf"=>"17", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2015", "month"=>"3"}
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- {"unique-ip"=>"31", "full-text"=>"29", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"5"}
- {"unique-ip"=>"21", "full-text"=>"28", "pdf"=>"16", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"14", "cited-by"=>"0", "year"=>"2015", "month"=>"6"}
- {"unique-ip"=>"14", "full-text"=>"16", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
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- {"unique-ip"=>"53", "full-text"=>"62", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"6", "cited-by"=>"2", "year"=>"2015", "month"=>"10"}
- {"unique-ip"=>"55", "full-text"=>"49", "pdf"=>"29", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"11"}
- {"unique-ip"=>"20", "full-text"=>"19", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
- {"unique-ip"=>"16", "full-text"=>"18", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
- {"unique-ip"=>"23", "full-text"=>"30", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
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- {"unique-ip"=>"20", "full-text"=>"20", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"6"}
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- {"unique-ip"=>"13", "full-text"=>"11", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
- {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
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- {"unique-ip"=>"24", "full-text"=>"25", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
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- {"unique-ip"=>"12", "full-text"=>"12", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"3", "cited-by"=>"1", "year"=>"2017", "month"=>"5"}
- {"unique-ip"=>"6", "full-text"=>"11", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"29", "supp-data"=>"22", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
- {"unique-ip"=>"10", "full-text"=>"13", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
- {"unique-ip"=>"11", "full-text"=>"13", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
- {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
- {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
- {"unique-ip"=>"12", "full-text"=>"15", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
- {"unique-ip"=>"12", "full-text"=>"13", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
- {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
- {"unique-ip"=>"14", "full-text"=>"12", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
- {"unique-ip"=>"12", "full-text"=>"13", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
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- {"unique-ip"=>"30", "full-text"=>"29", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
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- {"unique-ip"=>"16", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
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- {"unique-ip"=>"10", "full-text"=>"11", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
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- {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
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Relative Metric
{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Anatomy", "average_usage"=>[267]}, {"subject_area"=>"/Biology and life sciences/Toxicology", "average_usage"=>[266, 408]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[285]}, {"subject_area"=>"/Medicine and health sciences/Surgical and invasive medical procedures", "average_usage"=>[248, 388]}]}Loading … 

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