Severe neonatal hyperbilirubinemia in Crigler‐Najjar syndrome model mice can be reversed with zinc protoporphyrin

Abstract

Neurotoxic bilirubin is solely conjugated by UDP-glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase-I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1−/− mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin-induced neonatal lethality. Zinc protoporphyrin-treated Ugt1−/− mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down-regulated in a serum bilirubin level-dependent manner. Conclusion: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin-induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin.

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans

“…This insufficiency in the pharmacokinetic study with Ugt1 -null mice is largely attributed to the early lethality of Ugt1 -null mice [33]. Most recently, it was revealed that Ugt1 -null mice that were treated with zinc protoporphyrin, which is a heme oxygenase-I inhibitor, avoided their extremely early lethality and they all became adults [102]. This methodology will allow the creation of complete Ugt knockout mice and completely humanized UGT mice.…”

Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

“…). In cases of Crigler‐Najjar syndrome or Gunn rats where UGT1A1 is deficient, CYP1s play a role in the compensatory pathway of bilirubin metabolism …”

“…This biliverdin–bilirubin redox cycle has been proposed to amplify antioxidant potency dramatically, although its significance has also been questioned . Elevation of serum bilirubin levels exerts a great impact on gene expression, which may be associated with the beneficial effects of bilirubin.…”

Importância Do Diagnóstico Laboratorial Da Hiperbilirrubinemia Em Neonatos: Revisão De Literatura

“…A BL é uma substância apolar e lipolítica encontrada no plasma na forma não conjugada (indireta), sendo transportada pela albumina para o fígado até ser captada pelos hepatócitos e convertida em bilirrubina conjugada (direta), a qual é tóxica em níveis elevados (5) . Pigmento de coloração amarelada, produzido principalmente pelas hemeproteínas encontradas nas hemácias, a BL é um importante marcador bioquímico utilizado no diagnóstico e monitoramento de doenças hepáticas e hematológicas (6) .…”

“…Embora quase sempre benigna, a hiperbilirrubinemia em neonatos requer avaliação cuidadosa e monitoramento, visando identificar os RN que podem desenvolver encefalopatia bilirrubínica ou kernicterus, doenças que podem ocasionar a morte do RN (10)(11) . A encefalopatia bilirrubínica (ECB) é uma patologia relacionada às manifestações clínicas agudas da toxicidade da BL nas primeiras semanas de vida, enquanto kernicterus se refere às sequelas permanentes com comprometimento representado por deficiências tênues do neurodesenvolvimento (3)(4)(5)(6)(7)(8) .…”