{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:30:19Z","timestamp":1792236619554,"version":"4.4.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,3,16]]},"abstract":"\n High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human\n UGT1<\/jats:italic>\n locus, encoding all 9-\n UGT1A<\/jats:italic>\n genes including\n UGT1A1<\/jats:italic>\n , was expressed in\n \n Ugt1\n \u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice. Because the most common clinical condition associated with jaundice in adults is Gilbert\u2019s syndrome, which is characterized by an allelic polymorphism in the\n UGT1A1<\/jats:italic>\n promoter, hyperbilirubinemia was monitored in humanized\n UGT1<\/jats:italic>\n mice that expressed either the Gilbert\u2019s\n UGT1A1*28<\/jats:italic>\n allele [\n \n Tg(UGT1\n A1*28<\/jats:sup>\n )Ugt1\n \u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice] or the normal\n UGT1A1*1<\/jats:italic>\n allele [\n \n Tg(UGT1\n A1*1<\/jats:sup>\n )Ugt1\n \u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice]. Adult\n \n Tg(UGT1\n A1*28<\/jats:sup>\n )Ugt1\n \u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice expressed elevated levels of total bilirubin (TB) compared with\n \n Tg(UGT1\n A1*1<\/jats:sup>\n )Ugt1\n \u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice, confirming that the promoter polymorphism associated with the\n UGT1A1*28<\/jats:italic>\n allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert\u2019s\n UGT1A1*28<\/jats:italic>\n promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In \u223c10% of the humanized\n UGT1<\/jats:italic>\n mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the\n UGT1A1<\/jats:italic>\n gene in neonatal mice.\n <\/jats:p>","DOI":"10.1073\/pnas.0913290107","type":"journal-article","created":{"date-parts":[[2010,3,1]],"date-time":"2010-03-01T23:55:41Z","timestamp":1267487741000},"page":"5024-5029","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":98,"title":["Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the\n UDP glucuronosyltransferase 1<\/i>\n (\n UGT1<\/i>\n ) locus"],"prefix":"10.1073","volume":"107","author":[{"given":"Ryoichi","family":"Fujiwara","sequence":"first","affiliation":[{"name":"Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghia","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Tukey","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s005350070044"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2006.02.002"},{"key":"e_1_3_3_3_2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0065-3101(24)00052-5","article-title":"Bilirubin metabolism and kernicterus","volume":"44","author":"Gourley GR","year":"1997","unstructured":"GR Gourley, Bilirubin metabolism and kernicterus. Adv Pediatr 44, 173\u2013229 (1997).","journal-title":"Adv Pediatr"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2003.09.011"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1053\/siny.2002.0101"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.11.3613.bloodjournal84113613"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.40.1.581"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115829"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.9.6.703"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1746.1999.01984.x"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199511023331802"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328012d0da"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008438109725"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M709244200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300645200"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32403-1"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0109-y"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s001090050127"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250635"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5252.1126"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2005-0395"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jp.7211157"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9610(99)80105-6"},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1158\/1055-9965.EPI-03-0070","article-title":"Correlation between the UDP-glucuronosyltransferase (UGT1A1) TATAA box polymorphism and carcinogen detoxification phenotype: signfi-cantly decreased glucuronidating activity against benzo(a)pyrene-7,8-dihydrodiol(-) in liver microsomes from subjects with the UGT1A1*28 variant","volume":"13","author":"Fang JL","year":"2004","unstructured":"JL Fang, P Lazarus, Correlation between the UDP-glucuronosyltransferase (UGT1A1) TATAA box polymorphism and carcinogen detoxification phenotype: signfi-cantly decreased glucuronidating activity against benzo(a)pyrene-7,8-dihydrodiol(-) in liver microsomes from subjects with the UGT1A1*28 variant. Cancer Epidemiol Biomarkers Prev 13, 102\u2013109 (2004).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.16.5918"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.113.6.1776"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.252626999"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1013794407325"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2008.01.001"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2008.05388.x"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e31817d9be0"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506683200"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.013243"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0438010100"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610790200"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.006130"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0913290107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,24]],"date-time":"2024-03-24T10:39:33Z","timestamp":1711276773000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0913290107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,3]]},"references-count":36,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2010,3,16]]}},"alternative-id":["10.1073\/pnas.0913290107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0913290107","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,3]]},"assertion":[{"value":"2010-03-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}