Skip to main content

Advertisement

SpringerLink
Log in

Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Polidocanol is an effective sclerosing agent that consists of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol and is known to have a low risk of complications. However, since the compound has been proposed for the local treatment of liver diseases, the potential for topical hepatic side effects should be examined. Therefore, the new model of normothermic-hemoperfused isolated porcine slaughterhouse livers was used to examine polidocanol-hepatotoxicity encompassing the advantages of slaughterhouse organs to reduce animal experiments and autologous blood as an optimal perfusate. Polidocanol was administered via the hepatic artery and portal vein and the effects of the sclerosant on organ function parameters were compared with those in an untreated control group. In contrast to the untreated control organs, significant differences were found in the polidocanol group for parameters such as alanine aminotransferase or organ weight after perfusion. The most striking differences were found for hepatic bile flow, which dropped in the polidocanol group to 0.24±0.02 ml/min per 1000 g after administration of the compound compared with 3.80±1.08 ml/min per 1000 g in the control group. In summary, the present observations indicate a risk of hepatotoxic effects of polidocanol. Clinicians should be aware of this problem and the use of polidocanol for intrahepatic sclerosing should be restricted to specialized centers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4A,B

Similar content being viewed by others

References

  • Abouna GM, Ashcroft T, Hull C, Hodson A, Kirkley J, Walder DN (1969) The assessment of function of the isolated perfused porcine liver. Br J Surg 56:289–295

    CAS  PubMed  Google Scholar 

  • Conrad P, Malouf GM, Stacey MC (1995) The Australian polidocanol (aethoxysklerol) study. Results at 2 years. Dermatol Surg 21:334–336; discussion 337–338

    Article  CAS  PubMed  Google Scholar 

  • Conway JG, Popp JA, Thurman RG (1985) Microcirculation in periportal and pericentral regions of lobule in perfused rat liver. Am J Physiol 249: G449–G456

    CAS  PubMed  Google Scholar 

  • Dittrich S, Groneberg DA, von Loeper J, Lippek F, Hegemann O, Grosse-Siestrup C, Lange PE (2004) Influence of cold storage on renal ischemia reperfusion injury after non-heart-beating donor explantation. Nephron Exp Nephrol 96:e97–e102

    Article  PubMed  Google Scholar 

  • Drapanas T, Zemel R, Vang JO (1966) Hemodynamics of the isolated perfused pig liver: metabolism according to routes of perfusion and rates of flow. Ann Surg 164:522–537

    CAS  PubMed  Google Scholar 

  • Elmslie RG, Rao MM, Howe LA, Hall P (1971) Functional deficits in the isolated perfused pig liver. Surg Gynecol Obstet 133:89–92

    CAS  PubMed  Google Scholar 

  • Fehrenberg C, von Baeyer H, Unger V, Schmitt R, Haider W, Quarcoo D, Groneberg DA, Grosse-Siestrup C (2004) Protective effects of B2 preservation solution in comparison to a standard solution (histidine-tryptophan-ketoglutarate/Bretschneider) in a model of isolated autologous hemoperfused porcine kidney. Nephron Physiol 96:p52–p58

    Article  CAS  PubMed  Google Scholar 

  • Feied CF, Jackson JJ, Bren TS, Bond OB, Fernando CE, Young VC, Hashemiyoon RB (1994) Allergic reactions to polidocanol for vein sclerosis. Two case reports. J Dermatol Surg Oncol 20:466–468

    CAS  PubMed  Google Scholar 

  • Fischer TC, Hartmann P, Loser C, Springer J, Peiser C, Dinh QT, Fischer A, Groneberg DA (2001) Abundant expression of vasoactive intestinal polypeptide receptor VPAC2 mRNA in human skin. J Invest Dermatol 117:754–756

    Article  CAS  PubMed  Google Scholar 

  • Fischer TC, Dinh QT, Peiser C, Loser C, Fischer A, Groneberg DA (2002) Simultaneous detection of receptor mRNA and ligand protein in human skin tissues. J Cutan Pathol 29:65–71

    Article  PubMed  Google Scholar 

  • Groneberg DA, Hartmann P, Dinh QT, Fischer A (2001) Expression and distribution of vasoactive intestinal polypeptide receptor VPAC2 mRNA in human airways. Lab Invest 81:749–755

    CAS  PubMed  Google Scholar 

  • Groneberg DA, Doring F, Nickolaus M, Daniel H, Fischer A (2002a) Renal assimilation of short chain peptides: visualization of tubular peptide uptake. Pharm Res 19:1209–1214

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Doring F, Theis S, Nickolaus M, Fischer A, Daniel H (2002b) Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. Am J Physiol Endocrinol Metab 282:E1172–E1179

    CAS  PubMed  Google Scholar 

  • Groneberg DA, Eynott PR, Lim S, Oates T, Wu R, Carlstedt I, Roberts P, McCann B, Nicholson AG, Harrison BD, Chung KF (2002c) Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 40:367–373

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Eynott PR, Oates T, Lim S, Wu R, Carlstedt I, Nicholson AG, Chung KF (2002d) Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung. Respir Med 96:81–86

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Grosse-Siestrup C, Fischer A (2002e) In vitro models to study hepatotoxicity. Toxicol Pathol 30:394–399

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Peiser C, Dinh QT, Matthias J, Eynott PR, Heppt W, Carlstedt I, Witt C, Fischer A, Chung KF (2003a) Distribution of respiratory mucin proteins in human nasal mucosa. Laryngoscope 113:520–524

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Welker P, Fischer TC, Dinh QT, Grutzkau A, Peiser C, Wahn U, Henz BM, Fischer A (2003b) Down-regulation of vasoactive intestinal polypeptide receptor expression in atopic dermatitis. J Allergy Clin Immunol 111:1099–1105

    Article  CAS  PubMed  Google Scholar 

  • Grosse-Siestrup C, Nagel S, Unger V, Meissler M, Pfeffer J, Fischer A, Groneberg DA (2001) The isolated perfused liver: A new model using autologous blood and porcine slaughterhouse organs. J Pharmacol Toxicol Methods 46:163–168

    Article  CAS  PubMed  Google Scholar 

  • Grosse-Siestrup C, Fehrenberg C, von Baeyer H, Groneberg DA (2002a) Multiple-organ harvesting for models of isolated hemoperfused organs of slaughtered pigs. ALTEX 19:9–13

    PubMed  Google Scholar 

  • Grosse-Siestrup C, Pfeffer J, Unger V, Nagel S, Witt C, Fischer A, Groneberg DA (2002b) Isolated hemoperfused slaughterhouse livers as a valid model to study hepatotoxicity. Toxicol Pathol 30:749–754

    Article  CAS  PubMed  Google Scholar 

  • Grosse-Siestrup C, Unger V, Fehrenberg C, v Baeyer H, Fischer A, Schaper F, Groneberg DA (2002c) A model of isolated autologously hemoperfused porcine slaughterhouse kidneys. Nephron 92:414–421

    Article  PubMed  Google Scholar 

  • Grosse-Siestrup C, Wiemer PM, Fischer TC, Fehrenberg C, Unger V, Fischer A, Groneberg DA (2002d) Isolated hemoperfused porcine skin as a valid model to assess percutaneous absorption. J Invest Dermatol 119:197–199

    Article  CAS  PubMed  Google Scholar 

  • Grosse-Siestrup C, Unger V, Meissler M, Nagel S, Wussow A, Peiser C, Fischer A, Schmitt R, Groneberg DA (2003) Hemoperfused isolated porcine slaughterhouse kidneys as a valid model for pharmacological studies. J Pharm Sci 92:1147–1154

    Article  CAS  PubMed  Google Scholar 

  • Guex JJ (1993) Indications for the sclerosing agent polidocanol (aetoxisclerol dexo, aethoxisklerol kreussler). J Dermatol Surg Oncol 19:959–961

    CAS  PubMed  Google Scholar 

  • Guglielmi A, Ruzzenente A, Sandri M, Kind R, Lombardo F, Rodella L, Catalano F, de Manzoni G, Cordiano C (2002) Risk assessment and prediction of rebleeding in bleeding gastroduodenal ulcer. Endoscopy 34:778–786

    Article  CAS  PubMed  Google Scholar 

  • Guillouzo A (1998) Liver cell models in in vitro toxicology. Environ Health Perspect 106:511–532

    CAS  PubMed  Google Scholar 

  • Ham JM, Pirola RC, Elmslie RG (1969) Function of the isolated perfused pig liver. Surg Gynecol Obstet 129:470–474

    CAS  PubMed  Google Scholar 

  • Hanze J, Groneberg DA, Rose F, Hanisch A, Dotsch J, Peiser C, Seeger W, Rascher W, Fischer A, Grimminger F (2002) Genomic organization and regulation of a human 7-helix transmembrane receptor which is expressed in pulmonary epithelial cells and induced in hypoxia. Biochem Biophys Res Commun 291:1160–1165

    Article  PubMed  Google Scholar 

  • Heppt W, Peiser C, Cryer A, Dinh QT, Zweng M, Witt C, Fischer A, Groneberg DA (2002) Innervation of human nasal mucosa in environmentally triggered hyperreflectoric rhinitis. J Occup Environ Med 44:924–929

    Article  CAS  PubMed  Google Scholar 

  • Hochel J, Lehmann D, Fehrenberg C, Unger V, Groneberg DA, Grosse-Siestrup C (2003) Effects of different perfusates on functional parameters of isolated perfused dog kidneys. Nephrol Dial Transplant 18:1748–1754

    Article  PubMed  Google Scholar 

  • Jablonski P, Doglas MC, Gordon E, Owen JA, Watts JM (1971) Studies on the isolated perfused pig liver. Br J Surg 58:129–137

    CAS  PubMed  Google Scholar 

  • Jacob P, Rossmann H, Lamprecht G, Kretz A, Neff C, Lin-Wu E, Gregor M, Groneberg DA, Kere J, Seidler U (2002) Down-regulated in adenoma mediates apical Cl−/HCO3− exchange in rabbit, rat, and human duodenum. Gastroenterology 122:709–724

    CAS  PubMed  Google Scholar 

  • Kaneko T, Nakao A, Takagi H (2002) Clinical studies of new material for portal vein embolization: comparison of embolic effect with different agents. Hepatogastroenterology 49:472–477

    PubMed  Google Scholar 

  • Kerzel S, Path G, Nockher WA, Quarcoo D, Raap U, Groneberg DA, Dinh QT, Fischer A, Braun A, Renz H (2003) Pan-neurotrophin receptor p75 contributes to neuronal hyperreactivity and airway inflammation in a murine model of experimental asthma. Am J Respir Cell Mol Biol 28:170–178

    Article  CAS  PubMed  Google Scholar 

  • Lim S, Groneberg D, Fischer A, Oates T, Caramori G, Mattos W, Adcock I, Barnes PJ, Chung KF (2000) Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: effect of inhaled corticosteroids. Am J Respir Crit Care Med 162:1912–1918

    CAS  PubMed  Google Scholar 

  • Marrocco-Trischitta MM, Nicodemi EM, Stillo F (2001) Sclerotherapy for venous malformations of the glans penis. Urology 57:310–313

    Article  CAS  PubMed  Google Scholar 

  • Meren H, Varin F, Ruwart M, Thurman RG (1986) Effect of 16,16-dimethyl prostaglandin E2 on oxygen uptake and microcirculation in the perfused rat liver. Hepatology 6:917–921

    CAS  PubMed  Google Scholar 

  • Modersohn D, Eddicks S, Grosse-Siestrup C, Ast I, Holinski S, Konertz W (2001) Isolated hemoperfused heart model of slaughterhouse pigs. Int J Artif Organs 24:215–221

    CAS  PubMed  Google Scholar 

  • Morales P, Baum AE (2003) Therapeutic alternatives for the Mallory-Weiss tear. Curr Treat Options Gastroenterol 6:75–83

    PubMed  Google Scholar 

  • Morsiani E, Rimondi AP, Gorini P, Fogli L, Cappellari L, Gullini S (1987) Effect of intravenous and intraperivenous injections of sclerosants (sodium tetradecyl sulfate and hydroxy polyethoxy dodecan) on the rat femoral vein. Res Exp Med (Berl) 187:439–449

    Google Scholar 

  • Ormeci N, Soykan I, Bektas A, Sanoglu M, Palabiyikoglu M, Hadi Yasa M, Dokmeci A, Uzunalimoglu O (2001) A new percutaneous approach for the treatment of hydatid cysts of the liver. Am J Gastroenterol 96:2225–2230

    Article  CAS  PubMed  Google Scholar 

  • Parrish AR, Gandolfi AJ, Brendel K (1995) Precision-cut tissue slices: applications in pharmacology and toxicology. Life Sci 57:1887–1901

    Article  CAS  PubMed  Google Scholar 

  • Peiser C, Springer J, Groneberg DA, McGregor GP, Fischer A, Lang RE (2002) Leptin receptor expression in nodose ganglion cells projecting to the rat gastric fundus. Neurosci Lett 320:41–44

    Article  CAS  PubMed  Google Scholar 

  • Robertson CS, Womack C, Robson K, Morris DL (1989) A study of the local toxicity of agents used for variceal injection sclerotherapy. HPB Surg 1:149–152; discussion 153–144

    CAS  PubMed  Google Scholar 

  • Rubio-Aliaga I, Frey I, Boll M, Groneberg DA, Eichinger HM, Balling R, Daniel H (2003) Targeted disruption of the peptide transporter Pept2 gene in mice defines its physiological role in the kidney. Mol Cell Biol 23:3247–3252

    Article  CAS  PubMed  Google Scholar 

  • Sharara AI, Rockey DC (2001) Gastroesophageal variceal hemorrhage. N Engl J Med 345:669–681

    Article  CAS  PubMed  Google Scholar 

  • Springer J, Amadesi S, Trevisani M, Harrison S, Dinh QT, McGregor GP, Fischer A, Geppetti P, Groneberg DA (2004) Effects of α-calcitonin gene-related peptide in human bronchial smooth muscle and pulmonary artery. Regul Pept 118:127–134

    Article  CAS  PubMed  Google Scholar 

  • Ulrich RG, Bacon JA, Cramer CT, Peng GW, Petrella DK, Stryd RP, Sun EL (1995) Cultured hepatocytes as investigational models for hepatic toxicity: practical applications in drug discovery and development. Toxicol Lett 82–83:107–115

    Google Scholar 

  • Vlavianos P, Westaby D (2001) Management of acute variceal haemorrhage. Eur J Gastroenterol Hepatol 13:335–342

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant of the German Ministry of Education and Research (BMBF 0311021). We thank V. Essig for excellent technical assistance and O. Hegemann and B. Kloft for helpful discussions. We also gratefully acknowledge the organ support by Eberswalder Fleischwarenfabrik Plumrose Inc. abattoir, Britz, Germany.

Author information

Authors and Affiliations

  1. Department of Comparative Medicine and Experimental Animal Sciences, Charité School of Medicine, Free University and Humboldt-University, 13353, Berlin, Germany

    Christian Grosse-Siestrup, Volker Unger & Stefan Nagel

  2. Paul-Ehrlich-Institute, 63225, Langen, Germany

    Jeanette Pfeffer

  3. Department of Pediatric Pneumology and Immunology, Charité School of Medicine, Free University and Humboldt-University, 13353, Berlin, Germany

    Q. Thai Dinh & Jochen Springer

  4. Department of Medicine, Charité School of Medicine, Free University and Humboldt-University, 13353, Berlin, Germany

    Christian Witt & David A. Groneberg

  5. Institute of Occupational Medicine, University of Lübeck, 23538, Lübeck, Germany

    Anke Wussow

  6. Occupation and Environmental Medicine Research Group, Biomedical Research Center, Charité School of Medicine, Free University and Humboldt-University, Augustenburger Platz 1-OR-3, 13353, Berlin, Germany

    David A. Groneberg

Authors
  1. Christian Grosse-Siestrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Unger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeanette Pfeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Q. Thai Dinh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jochen Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Witt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anke Wussow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David A. Groneberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Groneberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grosse-Siestrup, C., Unger, V., Pfeffer, J. et al. Hepatotoxic effects of polidocanol in a model of autologously perfused porcine livers. Arch Toxicol 78, 697–705 (2004). https://doi.org/10.1007/s00204-004-0587-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-004-0587-7

Keywords

Search

Navigation