Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo

Remco van Dijk,Stan F. van de Graaf,Jurgen Seppen,Piter J. Bosma,Ulrich Beuers,Suzanne Duijst,Sem J. Aronson,Dirk R. de Waart,Ronald Oude Elferink

doi:10.1038/s41598-017-01602-w

Remco van Dijk, Stan F. van de Graaf + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-01602-w

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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.

Highlights

Severe unconjugated hyperbilirubinemia is a critical condition which can lead to irreversible brain damage already in early childhood and eventually can be lethal when left untreated[1]
Aiming to treat severe unconjugated hyperbilirubinemia by decreasing bilirubin production, we developed a screen for potential biliverdin reductase (BVRA) inhibitors
A second leukotriene receptor antagonist, Pranlukast (Onon), showed capacity to reduce BVRA activity by 50% during the drug library screen

Summary

Introduction

Severe unconjugated hyperbilirubinemia is a critical condition which can lead to irreversible brain damage (kernicterus) already in early childhood and eventually can be lethal when left untreated[1]. Accumulation of unconjugated bilirubin (UCB) results from an imbalance between UCB production and elimination and can be caused by several pathological conditions such as extensive hemolysis or severe impaired bilirubin glucuronidation known as Crigler-Najjar syndrome[2, 3]. Severe neonatal jaundice is in general caused by a combination of increased bilirubin production, due to extensive breakdown of fetal hemoglobin and a shorter life span of erythrocytes, and a reduced clearance of bilirubin due to low UGT1A1 expression in the newborn liver[8]. Crigler-Najjar syndrome (CNS) is an autosomal recessive disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of bilirubin glucuronidation, due to impaired or complete lack of UGT1A1 function[11]. Drawbacks of phototherapy are the long exposure time (up to 14 hours daily), and reduced efficacy over time Liver transplantation, both orthotopic and auxiliary, is currently the only curative therapy for CNS12, 13. Due to the risk for complications and mortality, the need of lifelong immunosuppression and the long waiting list, the use of liver transplantation in CNS has its limitations

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