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Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1(-/-) lethal mouse model of neonatal hyperbilirubinemia

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F17%3A10338099" target="_blank" >RIV/00216208:11110/17:10338099 - isvavai.cz</a>

  • Alternative codes found

    RIV/00064165:_____/17:10338099

  • Result on the web

    <a href="http://dx.doi.org/10.1093/hmg/ddw375" target="_blank" >http://dx.doi.org/10.1093/hmg/ddw375</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1093/hmg/ddw375" target="_blank" >10.1093/hmg/ddw375</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1(-/-) lethal mouse model of neonatal hyperbilirubinemia

  • Original language description

    Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown. To this end, we mated Abcb1a/b(-/-) and Abcc1(-/-) strains with Ugt1(-/-) mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1(-/-) mice survived after temporary phototherapy, all Abcb1a/b(-/-)/Ugt1(-/-) mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important. In the cerebellum of Ugt1(-/-) mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response. We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10608 - Biochemistry and molecular biology

Result continuities

  • Project

    <a href="/en/project/LH%2015097" target="_blank" >LH 15097: Molecular Basis of Bilirubin Neurotoxicity</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2017

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Human Molecular Genetics

  • ISSN

    0964-6906

  • e-ISSN

  • Volume of the periodical

    26

  • Issue of the periodical within the volume

    1

  • Country of publishing house

    GB - UNITED KINGDOM

  • Number of pages

    13

  • Pages from-to

    145-157

  • UT code for WoS article

    000397064600012

  • EID of the result in the Scopus database

    2-s2.0-85030230675