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J Hepatol. 2017 Aug;67(2):272-281. doi: 10.1016/j.jhep.2017.03.037. Epub 2017 Apr 12.

Impact of higher-order heme degradation products on hepatic function and hemodynamics.

Author information

1
Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany; Institute of Inorganic and Analytical Chemistry, Bioorganic Analytics, Friedrich Schiller University Jena, Germany.
2
HansPopper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
3
Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany.
4
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Germany.
5
Institute of Inorganic and Analytical Chemistry, Inorganic Chemistry I, Friedrich Schiller University Jena, Germany.
6
Electron Microscopy Center, Jena University Hospital, Germany.
7
HansPopper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria; Pediatric Gastroenterology and Hepatology, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, The Netherlands.
8
Institute of Inorganic and Analytical Chemistry, Bioorganic Analytics, Friedrich Schiller University Jena, Germany.
9
Department of Anesthesiology and Intensive Care Medicine/Center for Sepsis Control and Care, Jena University Hospital, Germany. Electronic address: michael.bauer@med.uni-jena.de.

Abstract

BACKGROUND & AIMS:

Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions.

METHODS:

Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia.

RESULTS:

Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton.

CONCLUSIONS:

Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia.

LAY SUMMARY:

Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.

KEYWORDS:

Bilirubin oxidation end products (BOXes); Bilirubin toxicity; Cholestasis; Cytoskeleton; Glutathione; Heme degradation; Hemodynamics; Pharmacokinetics; Reactive oxygen species; Rev-erb

PMID:
28412296
DOI:
10.1016/j.jhep.2017.03.037
[Indexed for MEDLINE]
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