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Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo.


ABSTRACT: We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity ?and 2?6 compounds were identified as BVRA inhibitors?. Montelukast and Disulfiram were sel?ected as potentially clinically applicable drug?s and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for chronic unconjugated hyperbilirubinemia. Oral administration of Disulfiram was toxic in the Ugt1a1-deficient rat (weight loss, transaminase elevation). Oral Montelukast administration led to low serum concentrations and did not alter serum UCB levels. Intraperitoneal injections of Mont?elukast resulted in concentrations up to 110??mol/L in serum and 400??mol/L in the liver. Still, serum UCB levels remained unaltered. This first study on biliverdin reductase inhibition as a novel concept for treatment of unconjugated hyperbilirubinemia identified putative in vitro BVRA inhibitors. Montelukast, the clinically most suitable inhibitor, did not result in reduction of serum UCB in the Ugt1a1-deficient rat. The proposed treatment strategy will not result in amelioration of severe unconjugated hyperbilirubinemia in humans without the identification or development of more potent BVRA inhibitors.

SUBMITTER: van Dijk R 

PROVIDER: S-EPMC5431759 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo.

van Dijk Remco R   Aronson Sem J SJ   de Waart Dirk R DR   van de Graaf Stan F SF   Duijst Suzanne S   Seppen Jurgen J   Elferink Ronald Oude RO   Beuers Ulrich U   Bosma Piter J PJ  

Scientific reports 20170510 1


We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity and 26 compounds were identified as BVRA inhibitors. Montelukast and Disulfiram were selected as potentially clinically applicable drugs and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for  ...[more]

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