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Archives of Toxicology

, Volume 89, Issue 11, pp 2069–2078 | Cite as

Optimality in the zonation of ammonia detoxification in rodent liver

  • Martin Bartl
  • Michael Pfaff
  • Ahmed Ghallab
  • Dominik Driesch
  • Sebastian G. Henkel
  • Jan G. Hengstler
  • Stefan Schuster
  • Christoph Kaleta
  • Rolf Gebhardt
  • Sebastian Zellmer
  • Pu Li
Organ Toxicity and Mechanisms

Abstract

The rodent liver eliminates toxic ammonia. In mammals, three enzymes (or enzyme systems) are involved in this process: glutaminase, glutamine synthetase and the urea cycle enzymes, represented by carbamoyl phosphate synthetase. The distribution of these enzymes for optimal ammonia detoxification was determined by numerical optimization. This in silico approach predicted that the enzymes have to be zonated in order to achieve maximal removal of toxic ammonia and minimal changes in glutamine concentration. Using 13 compartments, representing hepatocytes, the following predictions were generated: glutamine synthetase is active only within a narrow pericentral zone. Glutaminase and carbamoyl phosphate synthetase are located in the periportal zone in a non-homogeneous distribution. This correlates well with the paradoxical observation that in a first step glutamine-bound ammonia is released (by glutaminase) although one of the functions of the liver is detoxification by ammonia fixation. The in silico approach correctly predicted the in vivo enzyme distributions also for non-physiological conditions (e.g. starvation) and during regeneration after tetrachloromethane (CCl4) intoxication. Metabolite concentrations of glutamine, ammonia and urea in each compartment, representing individual hepatocytes, were predicted. Finally, a sensitivity analysis showed a striking robustness of the results. These bioinformatics predictions were validated experimentally by immunohistochemistry and are supported by the literature. In summary, optimization approaches like the one applied can provide valuable explanations and high-quality predictions for in vivo enzyme and metabolite distributions in tissues and can reveal unknown metabolic functions.

Keywords

Liver zonation Ammonia metabolism Glutamine synthetase Optimization Systems biology 

Abbreviations

CPS

Carbamoyl phosphate synthetase

CCl4

Tetrachloromethane

G

Glutamine

Glnase

Glutaminase

GS

Glutamine synthetase

Notes

Acknowledgments

Parts of this work have been supported by the German Virtual Liver Initiative (www.virtual-liver.de) of the German Federal Ministry of Education and Research (RG: 0315735, DD and SH: 0315760 and CK: 0315758) and the German Research Foundation (CK: KA 3541/3-1). We thank J. Schleicher, Ch. Tokarski and S. Vlaic for stimulating discussions.

Author contributions

MB, MP prepared and conducted the optimization. AG, JH prepared and conducted the experimental validation. MB, MP, SZ, PL conceived the main part of research. MB, SZ wrote the main part of manuscript. MP, AG, DD, SH, JH, SS, CK, RG involved in discussion and interpretation of results as well as writing parts of the manuscript.

Compliance with ethical standards

Ethical approval

All procedures were in accordance with the ethical standards of the institution.

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Martin Bartl
    • 1
    • 2
    • 3
  • Michael Pfaff
    • 4
    • 2
  • Ahmed Ghallab
    • 5
    • 6
  • Dominik Driesch
    • 2
  • Sebastian G. Henkel
    • 2
  • Jan G. Hengstler
    • 5
  • Stefan Schuster
    • 7
  • Christoph Kaleta
    • 1
    • 8
  • Rolf Gebhardt
    • 9
  • Sebastian Zellmer
    • 9
    • 10
  • Pu Li
    • 3
  1. 1.Research Group Theoretical Systems BiologyFriedrich Schiller University JenaJenaGermany
  2. 2.BioControl Jena GmbHJenaGermany
  3. 3.Department of Simulation and Optimal ProcessesIlmenau University of TechnologyIlmenauGermany
  4. 4.Department of Medical Engineering and BiotechnologyUniversity of Applied Sciences JenaJenaGermany
  5. 5.Leibniz Research Centre for Working Environment and Human FactorsDortmundGermany
  6. 6.Department of Forensic Medicine and Toxicology, Faculty of Veterinary MedicineSouth Valley UniversityQenaEgypt
  7. 7.Department of BioinformaticsFriedrich Schiller University JenaJenaGermany
  8. 8.Research Group Medical Systems Biology, Institute for Experimental MedicineChristian-Albrechts-University KielKielGermany
  9. 9.Institute of Biochemistry, Faculty of MedicineUniversity of LeipzigLeipzigGermany
  10. 10.Department of Chemicals and Product SafetyGerman Federal Institute for Risk Assessment (BfR)BerlinGermany

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