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

Ryoichi Fujiwara1, Nghia Nguyen, Shujuan Chen

  • 1Laboratory of Environmental Toxicology, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 3, 2010
PubMed

Insights

High unconjugated bilirubin (UCB) in newborns can cause brain damage. This study modeled UCB accumulation in mice, revealing neonatal UCB toxicity independent of Gilbert

Area of Science:

  • Biochemistry
  • Genetics
  • Neonatology

Background:

  • High unconjugated bilirubin (UCB) in newborns is linked to reduced hepatic UDP glucuronosyltransferase (UGT) 1A1 activity, potentially causing central nervous system (CNS) toxicity.
  • Mechanisms of UCB accumulation in brain tissue remain poorly understood.
  • Gilbert's syndrome, a common clinical condition, involves a UGT1A1 promoter polymorphism contributing to hyperbilirubinemia in adults.

Purpose of the Study:

  • To investigate the events leading to UCB accumulation in brain tissue by creating a mouse model.
  • To compare UCB levels in neonatal mice expressing either the Gilbert's UGT1A1*28 allele or the normal UGT1A1*1 allele.

Main Methods:

  • Humanized UGT1 mice expressing the human UGT1 locus (including UGT1A1) were generated in a Ugt1(-/-) background.
  • Mice carrying either the UGT1A1*28 (Gilbert's) or UGT1A1*1 (normal) promoter alleles were monitored for hyperbilirubinemia.
  • Total bilirubin (TB) levels were assessed during neonatal development and adulthood.

Main Results:

  • Adult humanized UGT1 mice with the UGT1A1*28 allele showed elevated TB compared to those with the UGT1A1*1 allele, confirming the polymorphism's role in hyperbilirubinemia.
  • Neonatal mice experienced TB accumulation to near-toxic levels, irrespective of the UGT1A1 promoter polymorphism.
  • Neonatal TB clearance was not correlated with hepatic UGT1A1 expression; approximately 10% of mice exhibited seizures and mortality due to UCB brain deposition.

Conclusions:

  • Neonatal hyperbilirubinemia and associated CNS toxicity in this model are independent of the Gilbert's syndrome UGT1A1 promoter polymorphism.
  • UCB deposition and seizures in neonatal mice are linked to developmental stages and can be mitigated by enhancing UGT1A1 gene regulation.

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