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

JOURNAL OF HEPATOLOGY

卷:67

Article

Seidel, Raphael A.^1,2  Claudel, Thierry³  Schleser, Franziska A.¹  Ojha, Navin K.^4,5  Westerhausen, Matthias⁶  Nietzsche, Sandor⁷  Sponholz, Christoph¹  Cuperus, Frans^3,8  Coldewey, Sina M.¹  Heinemann, Stefan H.^4,5  Pohnert, Georg²  Trauner, Michael³  Bauer, Michael¹ 

[1] Jena Univ Hosp, Ctr Sepsis Control & Care, Dept Anesthesiol & Intens Care Med, Jena, Germany

[2] Friedrich Schiller Univ Jena, Bioorgan Analyt, Inst Inorgan & Analyt Chem, Jena, Germany

[3] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, HansPopper Lab Mol Hepatol, Vienna, Austria

[4] Friedrich Schiller Univ Jena, Dept Biophys, Ctr Mol Biomed, Jena, Germany

[5] Jena Univ Hosp, Jena, Germany

[6] Friedrich Schiller Univ Jena, Inorgan Chem 1, Inst Inorgan & Analyt Chem, Jena, Germany

[7] Jena Univ Hosp, Electron Microscopy Ctr, Jena, Germany

[8] Univ Med Ctr Groningen, Ctr Liver Digest & Metab Dis, Pediat Gastroenterol & Hepatol, Groningen, Netherlands

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

DOI  :  10.1016/j.jhep.2017.03.037

来源: Elsevier

【 摘 要 】

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 similar to 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 similar to 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-erba and Rev-erbb. 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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

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