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Research ArticleDrug Discovery and Translational Medicine

An Ex Vivo Perfusion System Emulating In Vivo Conditions in Noncirrhotic and Cirrhotic Human Liver

Thomas Schreiter, Guido Marquitan, Malin Darnell, Jan-Peter Sowa, Martina Bröcker-Preuss, Tommy B. Andersson, Hideo A. Baba, Marcus Furch, Gavin E. Arteel, Zoltan Mathé, Jürgen Treckmann, Guido Gerken, Robert K. Gieseler and Ali Canbay
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 730-741; DOI: https://doi.org/10.1124/jpet.112.194167
Thomas Schreiter
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Guido Marquitan
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Malin Darnell
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Jan-Peter Sowa
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Martina Bröcker-Preuss
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Tommy B. Andersson
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Hideo A. Baba
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Marcus Furch
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Gavin E. Arteel
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Zoltan Mathé
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Jürgen Treckmann
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Guido Gerken
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Robert K. Gieseler
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Ali Canbay
Clinic for Gastroenterology and Hepatology, Center for Internal Medicine (T.S., G.M., J.-P.S., G.G., R.K.G., A.C.), Departments of Endocrinology and Clinical Chemistry and Laboratory Medicine (M.B.-P.), Institute for Pathology and Neuropathology (H.A.B.), and Clinic for General, Visceral, and Transplantation Surgery (Z.M., J.T.), University Hospital Essen, Essen, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden (M.D., T.B.A.); Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany (M.F., R.K.G.); and Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky (G.E.A.)
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Abstract

Various models are used for investigating human liver diseases and testing new drugs. However, data generated in such models have only limited relevance for in vivo conditions in humans. We present here an ex vivo perfusion system using human liver samples that enables the characterization of parameters in a functionally intact tissue context. Resected samples of noncirrhotic liver (NC; n = 10) and cirrhotic liver (CL; n = 12) were perfused for 6-h periods. General and liver-specific parameters (glucose, lactate, oxygen, albumin, urea, and bile acids), liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, and γ-glutamyl transferase), overall (M65) and apoptotic (M30) cell-death markers, and indicators of phase-I/phase-II biotransformations were analyzed. The measurement readings closely resembled (patho)physiological characteristics in patients with NC and CL. Mean courses of glucose levels reflected the CLs' reduced glycogen storage capability. Furthermore, CL samples exhibited significantly stronger increases in lactate, bile acids, and the M30/M65 ratio than NC specimens. Likewise, NC samples exhibited more rapid phase-I transformations of phenacetin, midazolam, and diclofenac and phase-I to phase-II turnover rates of the respective intermediates than CL tissue. Collectively, these findings reveal the better hepatic functionality in NC. Perfusion of human liver tissue with this system emulates in vivo conditions and clearly discriminates between noncirrhotic and cirrhotic tissue. This highly reliable device for investigating basic hepatic functionality and testing safety/toxicity, pharmacokinetics/pharmacodynamics and efficacies of novel therapeutic modalities promises to generate superior data compared with those obtained via existing economic perfusion systems.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grants CA267/6-1, CA267/8-1], the Wilhelm-Laupitz-Foundation (A.C.); and the Zentrales Innovationsprogramm Mittelstand program [Grants KF2531501AJ9 (to T.S., G.M., G.G., A.C.), KF2531701AJ9 (to M.F., R.K.G.)] by the Federal Ministry of Economics and Technology via the Consortium of Industrial Research Associations.

  • T.S., G.M., M.F., R.K.G., and A.C. have submitted a patent application specifying this perfusion system to the European Patent Office.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194167.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CL
    cirrhotic liver
    NC
    noncirrhotic liver
    AST
    aspartate aminotransferase
    ALT
    alanine aminotransferase
    LDH
    lactate dehydrogenase
    GLDH
    glutamate dehydrogenase
    γGT
    γ-glutamyl transferase
    ELISA
    enzyme-linked immunosorbent assay
    AUC
    area under the curve.

  • Received March 9, 2012.
  • Accepted June 1, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 3
1 Sep 2012
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Research ArticleDrug Discovery and Translational Medicine

Perfusion of Human Liver Sections

Thomas Schreiter, Guido Marquitan, Malin Darnell, Jan-Peter Sowa, Martina Bröcker-Preuss, Tommy B. Andersson, Hideo A. Baba, Marcus Furch, Gavin E. Arteel, Zoltan Mathé, Jürgen Treckmann, Guido Gerken, Robert K. Gieseler and Ali Canbay
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 730-741; DOI: https://doi.org/10.1124/jpet.112.194167

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Research ArticleDrug Discovery and Translational Medicine

Perfusion of Human Liver Sections

Thomas Schreiter, Guido Marquitan, Malin Darnell, Jan-Peter Sowa, Martina Bröcker-Preuss, Tommy B. Andersson, Hideo A. Baba, Marcus Furch, Gavin E. Arteel, Zoltan Mathé, Jürgen Treckmann, Guido Gerken, Robert K. Gieseler and Ali Canbay
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 730-741; DOI: https://doi.org/10.1124/jpet.112.194167
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