title: Modulation of bilirubin neurotoxicity by the Abcb1 transporter in the Ugt1-/- lethal mouse model of neonatal hyperbilirubinemia.
abstract: 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.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Luka
authors.initials: L
authors.lastname: Bockor
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bortolussi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Vodret
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iaconcig
authors.affiliation: Institute of Medical Biochemistry and Laboratory Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Jašprová
authors.affiliation: Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technicka 3, 166 28 Prague, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zelenka
authors.affiliation: Institute of Medical Biochemistry and Laboratory Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.|Fourth Department of Internal Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Vitek
authors.affiliation: Centro Studi Fegato, Fondazione Italiana Fegato, AREA Science Park, Campus Basovizza Trieste, Italy and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiribelli
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Andrés F
authors.initials: AF
authors.lastname: Muro
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000633:toxicity*; D002470:Cell Survival; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D014453:Glucuronosyltransferase / Q000502:physiology*; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000099148:UGT1A1 Enzyme
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001663:Bilirubin; D014453:Glucuronosyltransferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000099148:UGT1A1 Enzyme; C421109:multidrug resistance-associated protein 1