{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T20:45:01Z","timestamp":1783975501558,"version":"3.55.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1187,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,6]]},"abstract":"\n \n \n Gilbert syndrome (GS) is characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the white population. In GS the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects. The aim of this study was to characterize potential<\/jats:bold>\n in vivo<\/jats:bold>\n consequences of<\/jats:bold>\n UGT1A<\/jats:bold>\n gene variability in GS. Three hundred GS patients (UGT1A1*28 homozygous) and 249 healthy blood donors (HBD) were genotyped for<\/jats:bold>\n UGT1A<\/jats:bold>\n (UGT1A1*28,<\/jats:bold>\n UGT1A3<\/jats:bold>\n -\n 66 T>C, UGT1A6*3a, UGT1A7*3) and transporter single nucleotide polymorphisms (SNPs)<\/jats:bold>\n (\n SCLO1B1<\/jats:bold>\n p.V174A,<\/jats:bold>\n SCLO1B1<\/jats:bold>\n p.N130D,<\/jats:bold>\n ABCC2<\/jats:bold>\n p.I1324I,<\/jats:bold>\n ABCC2<\/jats:bold>\n -\n 24 UTR) using TaqMan-5\u2032-nuclease-assays. A humanized transgenic<\/jats:bold>\n UGT1A<\/jats:bold>\n -\n SNP and corresponding wildtype mouse model were established carrying the GS-associated<\/jats:bold>\n UGT1A<\/jats:bold>\n variant haplotype. UGT1A transcript and protein expression, and transcriptional activation were studied<\/jats:bold>\n in vivo<\/jats:bold>\n .\n Homozygous UGT1A1*28 GS individuals were simultaneously homozygous for UGT1A3\u201366 T>C (91%), UGT1A6*2a (77%), and UGT1A7*3 (77%). Seventy-six percent of GS and only 9% of HBD were homozygous for the variant haplotype spanning four<\/jats:bold>\n UGT1A<\/jats:bold>\n genes.<\/jats:bold>\n SCLO1B1<\/jats:bold>\n and<\/jats:bold>\n ABCC2<\/jats:bold>\n SNPs showed no differences. In transgenic humanized<\/jats:bold>\n UGT1A<\/jats:bold>\n SNP and wildtype mice this<\/jats:bold>\n UGT1A<\/jats:bold>\n haplotype led to lower UGT1A messenger RNA (mRNA) expression and UGT1A protein synthesis.<\/jats:bold>\n UGT1A<\/jats:bold>\n transcriptional activation by dioxin, phenobarbital, and endotoxin was significantly reduced in SNP mice.<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n Our data redefine the genetic basis behind GS.<\/jats:bold>\n In vivo<\/jats:bold>\n data studying the genotype present in 76% of GS individuals suggest that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and detoxification is directly affected, leading to lower responsiveness. This study suggests that GS should be considered a potential risk factor for drug toxicity.<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.25561","type":"journal-article","created":{"date-parts":[[2011,12,27]],"date-time":"2011-12-27T01:50:34Z","timestamp":1324950634000},"page":"1912-1921","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":45,"title":["Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation"],"prefix":"10.1097","volume":"55","author":[{"given":"Ursula","family":"Ehmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Kalthoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Fakundiny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Pabst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Freiberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Naumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Manns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Strassburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-28-20241201","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3109\/03602530903209429","article-title":"GilbertMeulengrachts syndrome and pharmacogenetics: is jaundice just the tip of the iceberg?","volume":"42","author":"Strassburg","year":"2010","journal-title":"Drug Metab Rev"},{"key":"R2-28-20241201","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1056\/NEJM199511023331802","article-title":"The genetic basis of the reduced expression of bilirubin UDPglucuronosyltransferase 1 in Gilberts syndrome.","volume":"333","author":"Bosma","year":"1995","journal-title":"N Engl J Med"},{"key":"R3-28-20241201","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/S0140-6736(96)91273-8","article-title":"Genetic variation in bilirubin UPDglucuronosyltransferase gene promoter and Gilberts syndrome.","volume":"347","author":"Monaghan","year":"1996","journal-title":"Lancet"},{"key":"R4-28-20241201","first-page":"2542","article-title":"Bilirubin UDPglucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem, 1994;269:17960-17964. erratum, J Biol Chem 1994 O","volume":"269","author":"Bosma","year":"14","journal-title":"ct"},{"key":"R5-28-20241201","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1023\/A:1008438109725","article-title":"UGT1A1 genotypes and glucuronidation of SN38, the active metabolite of irinotecan.","volume":"9","author":"Ando","year":"1998","journal-title":"Ann Oncol"},{"key":"R6-28-20241201","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1200\/JCO.2004.07.173","article-title":"Genetic variants in the UDPglucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.","volume":"22","author":"Innocenti","year":"2004","journal-title":"J Clin Oncol"},{"key":"R7-28-20241201","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1158\/1055-9965.EPI-07-2517","article-title":"Gilberts syndrome and irinotecan toxicity: combination with UDPglucuronosyltransferase 1A7 variants increases risk.","volume":"17","author":"Lankisch","year":"2008","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"R8-28-20241201","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1146\/annurev.pharmtox.40.1.581","article-title":"Human UDPglucuronosyltransferases: metabolism, expression, and disease.","volume":"40","author":"Tukey","year":"2000","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"R9-28-20241201","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1158\/1055-9965.EPI-03-0070","article-title":"Correlation between the UDPglucuronosyltransferase (UGT1A1) TATAA box polymorphism and carcinogen detoxification phenotype: significantly decreased glucuronidating activity against benzo(a)pyrene7,8dihydrodiol() in liver microsomes from subjects with the UGT1A128 variant.","volume":"13","author":"Fang","year":"2004","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"R10-28-20241201","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.jhep.2010.01.010","article-title":"Regulation of the human bile acid UDPglucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids.","volume":"52","author":"Erichsen","year":"2010","journal-title":"J Hepatol"},{"key":"R11-28-20241201","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.1074\/jbc.M109.075770","article-title":"Interaction between oxidative stress sensor Nrf2 and xenobioticactivated aryl hydrocarbon receptor in the regulation of the human phase II detoxifying UDPglucuronosyltransferase 1A10.","volume":"285","author":"Kalthoff","year":"2010","journal-title":"J Biol Chem"},{"key":"R12-28-20241201","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00204-008-0347-1","article-title":"Aryl hydrocarbon receptor (AhR)mediated regulation of the human estrogen and bile acid UDPGlucuronosyltransferase 1A3 gene.","volume":"82","author":"Lankisch","year":"2008","journal-title":"Arch Toxicol"},{"key":"R13-28-20241201","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1124\/mol.104.007146","article-title":"Identification and characterization of a functional TATA box polymorphism of the UDP glucuronosyltransferase 1A7 gene.","volume":"67","author":"Lankisch","year":"2005","journal-title":"Mol Pharmacol"},{"key":"R14-28-20241201","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.jhep.2008.12.030","article-title":"Gilberts syndrome and hyperbilirubinemia in protease inhibitor therapyan extended haplotype of genetic variants increases risk in indinavir treatment.","volume":"50","author":"Lankisch","year":"2009","journal-title":"J Hepatol"},{"key":"R15-28-20241201","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1002\/hep.21361","article-title":"Gilberts disease and atazanavir: from phenotype to UDPglucuronosyltransferase haplotype.","volume":"44","author":"Lankisch","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R16-28-20241201","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1136\/gut.50.6.851","article-title":"Polymorphisms of the UDPglucuronosyltransferase (UGT) 1A7 gene in colorectal cancer.","volume":"50","author":"Strassburg","year":"2002","journal-title":"Gut"},{"key":"R17-28-20241201","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0016-5085(99)70239-8","article-title":"UDPglucuronosyltransferase activity in human liver and colon.","volume":"116","author":"Strassburg","year":"1999","journal-title":"Gastroenterology"},{"key":"R18-28-20241201","doi-asserted-by":"crossref","first-page":"8719","DOI":"10.1074\/jbc.273.15.8719","article-title":"Expression of the UDPglucuronosyltransferase 1A locus in human colon. 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