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 26 compounds were identified a...

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Autores principales:	Remco van Dijk, Sem J. Aronson, Dirk R. de Waart, Stan F. van de Graaf, Suzanne Duijst, Jurgen Seppen, Ronald Oude Elferink, Ulrich Beuers, Piter J. Bosma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d12f4548a8564f6a914ed21b89937903
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spelling	oai:doaj.org-article:d12f4548a8564f6a914ed21b899379032021-12-02T15:05:49ZBiliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo10.1038/s41598-017-01602-w2045-2322https://doaj.org/article/d12f4548a8564f6a914ed21b899379032017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01602-whttps://doaj.org/toc/2045-2322Abstract 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 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 Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/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.Remco van DijkSem J. AronsonDirk R. de WaartStan F. van de GraafSuzanne DuijstJurgen SeppenRonald Oude ElferinkUlrich BeuersPiter J. BosmaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Remco van Dijk Sem J. Aronson Dirk R. de Waart Stan F. van de Graaf Suzanne Duijst Jurgen Seppen Ronald Oude Elferink Ulrich Beuers Piter J. Bosma Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
description	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 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 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 Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/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.
format	article
author	Remco van Dijk Sem J. Aronson Dirk R. de Waart Stan F. van de Graaf Suzanne Duijst Jurgen Seppen Ronald Oude Elferink Ulrich Beuers Piter J. Bosma
author_facet	Remco van Dijk Sem J. Aronson Dirk R. de Waart Stan F. van de Graaf Suzanne Duijst Jurgen Seppen Ronald Oude Elferink Ulrich Beuers Piter J. Bosma
author_sort	Remco van Dijk
title	Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
title_short	Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
title_full	Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
title_fullStr	Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
title_full_unstemmed	Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
title_sort	biliverdin reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d12f4548a8564f6a914ed21b89937903
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Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo

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