Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus

被引:93
作者
Fujiwara, Ryoichi
Nguyen, Nghia
Chen, Shujuan
Tukey, Robert H. [1 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, Lab Environm Toxicol, La Jolla, CA 92093 USA
关键词
Ugt1; knockout; kernicterus; bilirubin; UGT1A1*28; Gilbert's Syndrome; ORGANIC ANION TRANSPORTER; GILBERTS-SYNDROME; UDP-GLUCURONOSYLTRANSFERASE; BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE-1; BILIVERDIN REDUCTASE; GENETIC-BASIS; METABOLISM; EXPRESSION; RECEPTOR; DISEASE;
D O I
10.1073/pnas.0913290107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 UGT1 locus, encoding all 9-UGT1A genes including UGT1A1, was expressed in Ugt1(-/-) mice. Because the most common clinical condition associated with jaundice in adults is Gilbert's syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28))Ugt1(-/-) mice] or the normal UGT1A1*1 allele [Tg (UGT1(A1*1))Ugt1(-/-) mice]. Adult Tg(UGT1(A1*28))Ugt1(-/-) mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1(A1*1)) Ugt1(-/-) mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert's UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In similar to 10% of the humanized UGT1 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 UGT1A1 gene in neonatal mice.
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收藏
页码:5024 / 5029
页数:6
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