Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences
- 1 August 1999
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 30 (2), 476-484
- https://doi.org/10.1002/hep.510300205
Abstract
In Crigler‐Najjar type II patients and, recently, in Crigler‐Najjar type I patients treated with human hepatocyte cell therapy, phenobarbital has been used for reducing the serum bilirubin load. Its effect is attributed to induction of the enzyme required for hepatic bilirubin elimination, UDP‐glucuronosyltransferase, UGT1A1. This study investigated the expression and inducibility of UGT1A1 in human donor livers and their corresponding primary hepatocyte cultures. Immunoblot analysis using a specific antibody directed against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte donors exhibited a >50‐fold difference in UGT1A1 level. UGT1A1 protein level correlated strongly with both liver microsomal bilirubin UGT activity and liver UGT1A1 mRNA level (r2 = .82 and .72, respectively). Of the 4 patients with the lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence associated with Gilbert's syndrome, and the fourth was a heterozygote. The 3 donors with the highest levels had a history of phenytoin exposure. Hepatocytes isolated from the phenytoin‐exposed donors exhibited marked declines in UGT1A1 mRNA levels during culturing. Induction studies using hepatocytes treated for 48 hours with phenobarbital (2 mmol/L), oltipraz (50 μmol/L), or 3‐methylcholanthrene (2.5 μmol/L) revealed UGT1A1‐inducing effects of phenobarbital, oltipraz, and, in particular, 3‐methylcholanthrene. Our data suggest that both genetic and environmental factors play an important role in the marked interindividual variability in UGT1A1 expression. An understanding of these mechanisms could lead to advances in the pharmacological therapy of life‐threatening unconjugated hyperbilirubinemia.Keywords
This publication has 26 references indexed in Scilit:
- Treatment of the Crigler–Najjar Syndrome Type I with Hepatocyte TransplantationNew England Journal of Medicine, 1998
- Regulation of Dioxin Receptor Function by OmeprazolePublished by Elsevier BV ,1997
- HEPATOCYTE TRANSPLANTATION AS A BRIDGE TO ORTHOTOPIC LIVER TRANSPLANTATION IN TERMINAL LIVER FAILURETransplantation, 1997
- Induction of a rat liver benzo[a]pyrene-trans-7,8-dihydrodiol glucuronidating activity by oltipraz and beta-naphthoflavoneCarcinogenesis: Integrative Cancer Research, 1997
- Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.JCI Insight, 1996
- Higher Serum Bilirubin Is Associated With Decreased Risk for Early Familial Coronary Artery DiseaseArteriosclerosis, Thrombosis, and Vascular Biology, 1996
- The Genetic Basis of the Reduced Expression of Bilirubin UDP-Glucuronosyltransferase 1 in Gilbert's SyndromeNew England Journal of Medicine, 1995
- Drug-Responsive and Tissue-Specific Alternative Expression of Multiple First Exons in Rat UDP-Glucuronosyltransferase Family 1 (UGT1) Gene ComplexThe Journal of Biochemistry, 1995
- Different effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on glucuronide conjugation of various aglycones. Studies in Wistar and Gunn ratsToxicology and Applied Pharmacology, 1979
- Effect of phenobarbital and 3-methylcholanthrene pretreatment on guinea pig hepatic microsomal bilirubin glucuronyltransferase activityBiochemical Pharmacology, 1971