Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGTLA1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

被引:97
作者
Ritter, JK
Kessler, FK
Thompson, ET
Grove, AD
Auyeung, DJ
Fisher, RA
机构
[1] Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Med Coll Virginia, Dept Surg, Richmond, VA 23298 USA
关键词
D O I
10.1002/hep.510300205
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 (r(2) = .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 (mu mol/L), or 3-methylcholanthrene (2.5 mu mol/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.
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页码:476 / 484
页数:9
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