{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T19:53:22Z","timestamp":1783626802630,"version":"3.55.0"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Exp Pharma Physio"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We have previously shown that hemeoxygenase\u20101 (HO1) induction and resulting elevation of bilirubin (BR) protects the liver from oxidative stress (OS)\u2010induced acute cholestasis in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To characterise the protective role of BR at the early\u2010to\u2010intermediate stages of obstructive cholestasis by investigating the consequences of inhibiting BR generation in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Zinc protoporphyrin IX (ZnPP), a HO1 inhibitor, was administered 24\u2009h before BDL to male Wistar rats. After confirming establishment of obstructive cholestasis and successful impairment in BR generation, we studied the impact of these interventions on redox status and histopathological features in liver tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OS biomarkers were significantly elevated in ZnPP\u2010pretreated BDL animals versus BDL\u2010only controls, showing that under cholestatic conditions, oxidative damage is increased when BR production is impaired. Levels of antioxidant defences were lower in animals lacking BR generation, indicating that hepatic oxidative damage is more severe and antioxidant defences are weaker when BR production is inhibited. Histopathological analysis revealed significantly more severe obstructive injury in HO1\u2010inhibited animals than in those subjected to BDL alone, indicating that BR generation impairment worsens the outcome of obstructive injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The inhibition of HO1 and consequent decrease in the endogenous levels of BR negatively impacts the outcome of obstructive cholestasis due to the loss of BR's antioxidant and cytoprotective effects. BR accumulation during cholestasis serves as a critical defence against oxidative damage induced by retained bile salts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/1440-1681.70123","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T13:45:23Z","timestamp":1775655923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of Bilirubin Generation Exacerbates Oxidative Stress and Liver Injury in Early\u2010to\u2010Intermediate Obstructive Cholestasis"],"prefix":"10.1111","volume":"53","author":[{"given":"Pamela L.","family":"Mart\u00edn","sequence":"first","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental (IFISE\u2010CONICET)  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine L.","family":"Hillotte","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental (IFISE\u2010CONICET)  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda V.","family":"Razori","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Experimental (IFISE\u2010CONICET)  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefan\u00eda M. 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