{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:17:05Z","timestamp":1776327425673,"version":"3.50.1"},"reference-count":29,"publisher":"Proceedings of the National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,12,10]]},"abstract":"<jats:p>\n            Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H\n            <jats:sub>2<\/jats:sub>\n            O\n            <jats:sub>2<\/jats:sub>\n            . We report that bilirubin is a major physiologic antioxidant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.\n          <\/jats:p>","DOI":"10.1073\/pnas.252626999","type":"journal-article","created":{"date-parts":[[2002,12,10]],"date-time":"2002-12-10T17:42:57Z","timestamp":1039542177000},"page":"16093-16098","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":896,"title":["Biliverdin reductase: A major physiologic cytoprotectant"],"prefix":"10.1073","volume":"99","author":[{"given":"David E.","family":"Bara\u00f1ano","sequence":"first","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Medicine, Division of Gastroenterology, C-2104 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2279"}]},{"given":"Mahil","family":"Rao","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Medicine, Division of Gastroenterology, C-2104 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2279"}]},{"given":"Christopher D.","family":"Ferris","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Medicine, Division of Gastroenterology, C-2104 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2279"}]},{"given":"Solomon H.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and Department of Medicine, Division of Gastroenterology, C-2104 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2279"}]}],"member":"341","published-online":{"date-parts":[[2002,11,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01931429"},{"key":"e_1_3_3_2_2","first-page":"64","volume":"89","author":"Schmid R.","year":"1976","unstructured":"Schmid R. 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