{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T13:01:45Z","timestamp":1767963705042,"version":"3.49.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T00:00:00Z","timestamp":1502323200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>Neurotoxic bilirubin is solely conjugated by UDP\u2010glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk\u2010induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the<jats:italic toggle=\"yes\">Ugt1<\/jats:italic>locus. Deletion of<jats:italic toggle=\"yes\">Ugt1a1<\/jats:italic>results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase\u2010I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn<jats:italic toggle=\"yes\">Ugt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin\u2010induced neonatal lethality. Zinc protoporphyrin\u2010treated<jats:italic toggle=\"yes\">Ugt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down\u2010regulated in a serum bilirubin level\u2010dependent manner.<\/jats:p><jats:p><jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin\u2010induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic>2017;1:792\u2013802)<\/jats:p>","DOI":"10.1002\/hep4.1082","type":"journal-article","created":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T09:22:49Z","timestamp":1502356969000},"page":"792-802","source":"Crossref","is-referenced-by-count":10,"title":["Severe neonatal hyperbilirubinemia in Crigler\u2010Najjar syndrome model mice can be reversed with zinc protoporphyrin"],"prefix":"10.1097","volume":"1","author":[{"given":"Ryoichi","family":"Fujiwara","sequence":"first","affiliation":[{"name":"Dr. Margarete Fischer\u2010Bosch Institute of Clinical Pharmacology,Stuttgart,Germany"},{"name":"Department of Biochemistry and Pharmacy,University of T\u00fcbingen,T\u00fcbingen,Germany"},{"name":"Department of Pharmaceutics, School of Pharmacy,Kitasato University,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Mitsugi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy,Kitasato University,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asuka","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy,Kitasato University,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoo","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy,Kitasato University,Tokyo,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Tukey","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Toxicology, Department of Pharmacology,University of California San Diego,La Jolla,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2017,8,10]]},"reference":[{"key":"hep41082-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"6388","DOI":"10.1016\/S0021-9258(18)63477-5","article-title":"Microsomal heme oxygenase. Characterization of the enzyme","volume":"244","year":"1969","journal-title":"J Biol Chem"},{"key":"hep41082-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"16093","DOI":"10.1073\/pnas.252626999","article-title":"Biliverdin reductase: a major physiologic cytoprotectant","volume":"99","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep41082-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1542\/peds.113.6.1776","article-title":"Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle","volume":"113","year":"2004","journal-title":"Pediatrics"},{"key":"hep41082-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1056\/NEJM199511023331802","article-title":"The genetic basis of the reduced expression of bilirubin UDP\u2010glucuronosyltransferase 1 in Gilbert's syndrome","volume":"333","year":"1995","journal-title":"N Engl J Med."},{"key":"hep41082-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/S0026-895X(25)13648-1","article-title":"Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat","volume":"43","year":"1993","journal-title":"Mol Pharmacol."},{"key":"hep41082-bib-0006-20240114","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.taap.2015.08.018","article-title":"Role of extrahepatic UDP\u2010glucuronosyltransferase 1A1: Advances in understanding breast milk\u2010induced neonatal hyperbilirubinemia","volume":"289","year":"2015","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep41082-bib-0007-20240114","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1002\/hep.1840150531","article-title":"Sequence of exons and the flanking regions of human bilirubin\u2010UDP\u2010glucuronosyltransferase gene complex and identification of a genetic mutation in a patient with Crigler\u2010Najjar syndrome, type I","volume":"15","year":"1992","journal-title":"Hepatology."},{"key":"hep41082-bib-0008-20240114","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0095-5108(18)30577-3","article-title":"The neurotoxicity of bilirubin","volume":"17","year":"1990","journal-title":"Clin Perinatol."},{"key":"hep41082-bib-0009-20240114","doi-asserted-by":"crossref","first-page":"7901","DOI":"10.1074\/jbc.M709244200","article-title":"Disruption of the ugt1 locus in mice resembles human Crigler\u2010Najjar type I disease","volume":"283","year":"2008","journal-title":"J Biol Chem"},{"key":"hep41082-bib-0010-20240114","doi-asserted-by":"crossref","first-page":"5024","DOI":"10.1073\/pnas.0913290107","article-title":"Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus","volume":"107","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep41082-bib-0011-20240114","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1096\/fj.11-195461","article-title":"Rescue of bilirubin\u2010induced neonatal lethality in a mouse model of Crigler\u2010Najjar syndrome type I by AAV9\u2010mediated gene transfer","volume":"26","year":"2012","journal-title":"FASEB J"},{"key":"hep41082-bib-0012-20240114","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1021\/bc020010k","article-title":"Pegylated zinc protoporphyrin: a water\u2010soluble heme oxygenase inhibitor with tumor\u2010targeting capacity","volume":"13","year":"2002","journal-title":"Bioconjug Chem"},{"key":"hep41082-bib-0013-20240114","doi-asserted-by":"crossref","first-page":"37547","DOI":"10.1074\/jbc.M506683200","article-title":"Tissue\u2010specific, inducible, and hormonal control of the human UDP\u2010glucuronosyltransferase\u20101 (UGT1) locus","volume":"280","year":"2005","journal-title":"J Biol Chem"},{"key":"hep41082-bib-0014-20240114","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1093\/bioinformatics\/bti551","article-title":"BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks","volume":"21","year":"2005","journal-title":"Bioinformatics"},{"key":"hep41082-bib-0015-20240114","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","year":"2009","journal-title":"Nat Protoc"},{"key":"hep41082-bib-0016-20240114","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1124\/dmd.115.063719","article-title":"Expression of UDP\u2010glucuronosyltransferase 1 (UGT1) and glucuronidation activity toward endogenous substances in humanized UGT1 mouse brain","volume":"43","year":"2015","journal-title":"Drug Metab Dispos"},{"key":"hep41082-bib-0017-20240114","doi-asserted-by":"crossref","first-page":"5251","DOI":"10.1038\/srep05251","article-title":"Expression of human solute carrier family transporters in skin: possible contributor to drug\u2010induced skin disorders","volume":"4","year":"2014","journal-title":"Sci Rep"},{"key":"hep41082-bib-0018-20240114","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1124\/mol.116.104174","article-title":"Induction of the UDP\u2010glucuronosyltransferase 1A1 during the perinatal period can cause neurodevelopmental toxicity","volume":"90","year":"2016","journal-title":"Mol Pharmacol"},{"key":"hep41082-bib-0019-20240114","doi-asserted-by":"crossref","first-page":"35633","DOI":"10.1038\/srep35633","article-title":"Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL\u201060 cells","volume":"6","year":"2016","journal-title":"Sci Rep"},{"key":"hep41082-bib-0020-20240114","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1172\/JCI112398","article-title":"Sn\u2010protoporphyrin inhibition of fetal and neonatal brain heme oxygenase. Transplacental passage of the metalloporphyrin and prenatal suppression of hyperbilirubinemia in the newborn animal","volume":"77","year":"1986","journal-title":"J Clin Invest."},{"key":"hep41082-bib-0021-20240114","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.siny.2014.12.008","article-title":"The clinical syndrome of bilirubin\u2010induced neurologic dysfunction","volume":"20","year":"2015","journal-title":"Semin Fetal Neonatal Med"},{"issue":"Suppl. 1","key":"hep41082-bib-0022-20240114","first-page":"86","article-title":"Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels","volume":"74","year":"2013","journal-title":"Pediatr Res"},{"key":"hep41082-bib-0023-20240114","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/pr.2015.207","article-title":"Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model","volume":"79","year":"2016","journal-title":"Pediatr Res"},{"key":"hep41082-bib-0024-20240114","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jhbp.245","article-title":"Recent advancement of molecular mechanisms of liver fibrosis","volume":"22","year":"2015","journal-title":"J Hepatobiliary Pancreat Sci"},{"key":"hep41082-bib-0025-20240114","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1053\/j.gastro.2012.02.003","article-title":"Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep41082-bib-0026-20240114","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.atherosclerosis.2008.07.021","article-title":"Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents","volume":"203","year":"2009","journal-title":"Atherosclerosis"},{"key":"hep41082-bib-0027-20240114","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/MPG.0b013e318291fefe","article-title":"Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children","volume":"57","year":"2013","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"hep41082-bib-0028-20240114","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.metabol.2013.01.011","article-title":"Serum bilirubin levels are lower in overweight asymptomatic middle\u2010aged adults: an early indicator of metabolic syndrome?","volume":"62","year":"2013","journal-title":"Metabolism"},{"key":"hep41082-bib-0029-20240114","first-page":"55","article-title":"The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases","volume":"3","year":"2012","journal-title":"Front Pharmacol"},{"key":"hep41082-bib-0030-20240114","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/ki.2010.265","article-title":"Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase","volume":"78","year":"2010","journal-title":"Kidney Int"},{"key":"hep41082-bib-0031-20240114","doi-asserted-by":"crossref","first-page":"E244","DOI":"10.1152\/ajpendo.00396.2016","article-title":"Mice with hyperbilirubinemia due to Gilbert's Syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARalpha","volume":"312","year":"2017","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"hep41082-bib-0032-20240114","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1203\/01.PDR.0000141846.37253.AF","article-title":"Risk factors for severe hyperbilirubinemia in neonates","volume":"56","year":"2004","journal-title":"Pediatr Res"},{"key":"hep41082-bib-0033-20240114","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1053\/j.gastro.2011.09.045","article-title":"Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF\u2010\u03baB leads to hyperbilirubinemia","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep41082-bib-0034-20240114","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1038\/srep02903","article-title":"Impact of fatty acids on human UDP\u2010glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia","volume":"3","year":"2013","journal-title":"Sci Rep"},{"key":"hep41082-bib-0035-20240114","doi-asserted-by":"crossref","first-page":"6343","DOI":"10.1038\/srep06343","article-title":"Glucose induces intestinal human UDP\u2010glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia","volume":"4","year":"2014","journal-title":"Sci Rep"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep4.1082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1082","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1082","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/02009842-201710000-00009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T21:41:13Z","timestamp":1750801273000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/02009842-201710000-00009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,10]]},"references-count":35,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1082","relation":{},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,10]]}}}