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Tytuł pozycji:

Activation of Alternative Bilirubin Clearance Pathways Partially Reduces Hyperbilirubinemia in a Mouse Model Lacking Functional Ugt1a1 Activity.

Tytuł:
Activation of Alternative Bilirubin Clearance Pathways Partially Reduces Hyperbilirubinemia in a Mouse Model Lacking Functional Ugt1a1 Activity.
Autorzy:
Banerjee B; Mouse Molecular Genetics Group, ICGEB, Padriciano, 99, 34149 Trieste, Italy.
Olajide OJ; Mouse Molecular Genetics Group, ICGEB, Padriciano, 99, 34149 Trieste, Italy.
Bortolussi G; Mouse Molecular Genetics Group, ICGEB, Padriciano, 99, 34149 Trieste, Italy.
Muro AF; Mouse Molecular Genetics Group, ICGEB, Padriciano, 99, 34149 Trieste, Italy.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2022 Sep 14; Vol. 23 (18). Date of Electronic Publication: 2022 Sep 14.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Bilirubin*
Hyperbilirubinemia*
Animals ; Disease Models, Animal ; Glucuronosyltransferase/genetics ; Glucuronosyltransferase/metabolism ; Heme/metabolism ; Liver/metabolism ; Mice
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Contributed Indexing:
Keywords: TCPOBOP; bilirubin-degradation pathways; constitutive androstane receptor (CAR); liver
Substance Nomenclature:
42VZT0U6YR (Heme)
EC 2.4.1.17 (Glucuronosyltransferase)
RFM9X3LJ49 (Bilirubin)
Entry Date(s):
Date Created: 20220923 Date Completed: 20220926 Latest Revision: 20220928
Update Code:
20240104
PubMed Central ID:
PMC9505366
DOI:
10.3390/ijms231810703
PMID:
36142606
Czasopismo naukowe
Bilirubin is a heme catabolite and Ugt1a1 is the only enzyme involved in the biological elimination of bilirubin. Partially functional or non-functional Ugt1a1 may result in neuronal damage and death due to the accumulation of unconjugated bilirubin in the brain. The understanding of the role of alternative bilirubin detoxification mechanisms that can reduce bilirubin toxicity risk is crucial for developing novel therapeutic strategies. To provide a proof-of-principle showing whether activation of alternative detoxification pathways could lead to life-compatible bilirubin levels in the absence of Ugt1a1 activity, we used Ugt1 -/- hyperbilirubinemic mice devoid of bilirubin glucuronidation activity. We treated adult Ugt1 -/- mice with TCPOBOP, a strong agonist of the constitutive androstane receptor (CAR). TCPOBOP treatment decreased plasma and liver tissue bilirubin levels by about 38%, and resulted in the transcriptional activation of a vast array of genes involved in bilirubin transport and metabolism. However, brain bilirubin level was unaltered. We observed ~40% degradation of bilirubin in the liver microsomes from TCPOBOP treated Ugt1 -/- mice. Our findings suggest that, in the absence of Ugt1a1, the activation of alternative bilirubin clearance pathways can partially improve hyperbilirubinemic conditions. This therapeutic approach may only be considered in a combinatorial manner along with other treatments.
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