Hepatotoxicity of immunotoxins made with saporin, a ribosome-inactivating protein from Saponaria officinalis

Fiorenzo Stirpe, Massimo Derenzini, Luigi Barbieri, Fulvia Farabegoli, Alex N F Brown, Philip P. Knowles, Philip E. Thorpe

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Immunotoxins were prepared by conjugating saporin, a ribosome-inactivating protein from Saponaria officinalis, to a monoclonal antibody against the Thy 1.1 antigen, or to its F(ab′)2 fragment. The immunotoxins were eight- to 16-fold more toxic to mice than free saporin. Injection of the immunotoxins induced necrosis of the liver and spleen, whereas free saporin caused necrosis of the epithelium of the kidney tubules. The cytoplasm of the hepatic parenchymal cells was affected by the immunotoxins, lesions being apparent in the rough endoplasmic reticulum and, later, in the mitochondria. These changes were associated with a reduced capacity to synthesise proteins both in the intact liver and by isolated liver microsomes. Studies of the in vivo distribution showed that 90% of the free saporin was removed from the bloodstream, mainly by the kidneys, within 10 min of injection. By contrast, the immunotoxins persisted in the blood for several hours and the only organ in which they consistently accumulated was the liver. The hepatotoxic effect of the immunotoxins was not due to their binding to liver cells via the antigen-binding sites or the Fc-piece of the antibody moiety, nor was it due to hepatic recognition of carbohydrate in the immunotoxin. It is concluded that free saporin, although capable of entering liver cells, is filtered so rapidly by the kidney that liver damage does not occur to a significant extent. Filtered saporin, however, is reabsorbed by renal tubules, whose epithelial cells are damaged. The antibody-saporin conjugate is too large to filter at the glomerulus and so has greater opportunity to penetrate into and to damage the hepatic parenchymal cell.

Original languageEnglish (US)
Pages (from-to)259-271
Number of pages13
JournalVirchows Archiv B Cell Pathology Including Molecular Pathology
Volume53
Issue number1
DOIs
StatePublished - Dec 1987

Fingerprint

Saponaria
Ribosome Inactivating Proteins
Immunotoxins
Liver
Kidney
Hepatocytes
Necrosis
Thy-1 Antigens
Kidney Tubules
Injections
Antibodies
Rough Endoplasmic Reticulum
Poisons
Liver Microsomes
saporin
Mitochondria
Cytoplasm
Spleen
Epithelium
Epithelial Cells

Keywords

  • Immunotoxins, in vivo effects
  • Monoclonal antibody conjugates
  • Ribosome-inactivating proteins
  • Saporin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Hepatotoxicity of immunotoxins made with saporin, a ribosome-inactivating protein from Saponaria officinalis. / Stirpe, Fiorenzo; Derenzini, Massimo; Barbieri, Luigi; Farabegoli, Fulvia; Brown, Alex N F; Knowles, Philip P.; Thorpe, Philip E.

In: Virchows Archiv B Cell Pathology Including Molecular Pathology, Vol. 53, No. 1, 12.1987, p. 259-271.

Research output: Contribution to journalArticle

Stirpe, Fiorenzo ; Derenzini, Massimo ; Barbieri, Luigi ; Farabegoli, Fulvia ; Brown, Alex N F ; Knowles, Philip P. ; Thorpe, Philip E. / Hepatotoxicity of immunotoxins made with saporin, a ribosome-inactivating protein from Saponaria officinalis. In: Virchows Archiv B Cell Pathology Including Molecular Pathology. 1987 ; Vol. 53, No. 1. pp. 259-271.
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AU - Thorpe, Philip E.

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