{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:32:06Z","timestamp":1792675926033,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>Biliatresone is an electrophilic isoflavone isolated from <jats:italic toggle=\"yes\">Dysphania<\/jats:italic> species plants that has been causatively linked to naturally occurring outbreaks of a biliary atresia (BA)\u2010like disease in livestock. Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHCs) in zebrafish larvae. To better understand its mechanism of toxicity, we performed transcriptional profiling of liver cells isolated from zebrafish larvae at the earliest stage of biliatresone\u2010mediated biliary injury, with subsequent comparison of biliary and hepatocyte gene expression profiles. Transcripts encoded by genes involved in redox stress response, particularly those involved in glutathione (GSH) metabolism, were among the most prominently up\u2010regulated in both cholangiocytes and hepatocytes of biliatresone\u2010treated larvae. Consistent with these findings, hepatic GSH was depleted at the onset of biliary injury, and <jats:italic toggle=\"yes\">in situ<\/jats:italic> mapping of the hepatic GSH redox potential using a redox\u2010sensitive green fluorescent protein biosensor showed that it was significantly more oxidized in EHCs both before and after treatment with biliatresone. Pharmacological and genetic manipulation of GSH redox homeostasis confirmed the importance of GSH in modulating biliatresone\u2010induced injury given that GSH depletion sensitized both EHCs and the otherwise resistant intrahepatic cholangiocytes to the toxin, whereas replenishing GSH level by <jats:italic toggle=\"yes\">N\u2010<\/jats:italic>acetylcysteine administration or activation of nuclear factor erythroid 2\u2010like 2 (Nrf2), a transcriptional regulator of GSH synthesis, inhibited EHC injury. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These findings strongly support redox stress as a critical contributing factor in biliatresone\u2010induced cholangiocyte injury, and suggest that variations in intrinsic stress responses underlie the susceptibility profile. Insufficient antioxidant capacity of EHCs may be critical to early pathogenesis of human BA. (H<jats:sc>epatology<\/jats:sc> 2016;64:894\u2010907)<\/jats:p>","DOI":"10.1002\/hep.28603","type":"journal-article","created":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T07:23:53Z","timestamp":1461309833000},"page":"894-907","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":54,"title":["Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish"],"prefix":"10.1097","volume":"64","author":[{"given":"Xiao","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Lorent","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,Children's Hospital of Philadelphia,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan M.","family":"Marchione","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orith","family":"Waisbourd\u2010Zinman","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Children's Hospital of Philadelphia,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhoon","family":"So","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology,McGowan Institute for Regenerative Medicine,University of Pittsburgh,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Ah","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences,University of the Sciences,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghun","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology,McGowan Institute for Regenerative Medicine,University of Pittsburgh,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Biological 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