A polyamine analogue prevents acute pancreatitis and restores early liver regeneration in transgenic rats with activated polyamine catabolism.

Abstract

We recently generated a transgenic rat model for acute pancreatitis, which was apparently caused by a massive depletion of pancreatic polyamines spermidine and spermine due to inducible activation of their catabolism (Alhonen, L., Parkkinen, J. J., Keinänen, T., Sinervirta, R., Herzig, K. H., and Jänne, J. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8290-8295). When subjected to partial hepatectomy, these animals showed striking activation of polyamine catabolism at 24 h postoperatively with a profound decrease in hepatic spermidine and spermine pools and failure to initiate liver regeneration. Here we show that pancreatitis in this model could be totally prevented, as judged by histopathology and plasma alpha-amylase activity, by administration of 1-methylspermidine, a metabolically stable analogue of spermidine. Similarly, the analogue, given prior to partial hepatectomy, restored early liver regeneration in the transgenic rats, as indicated by a dramatic increase in the number of proliferating cell nuclear antigen-positive hepatocytes from about 1% to more than 40% in response to the drug. The present results suggest that the extremely high concentration of spermidine in the pancreas, in fact the highest in the mammalian body, may have a critical role in maintaining organ integrity. The failure to initiate liver regeneration in the absence of sufficient hepatic polyamine pools similarly indicates that polyamines are required for proper commencement of the regenerative process.

• Authors: Tiina-Liisa Rasanen, Leena Alhonen, Riitta Sinervirta, Tuomo Keinanen, Karl-Heinz Herzig, Suvikki Suppola, Alex R Khomutov, Jouko Vepsalainen, Juhani Janne
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 42 Pg. 39867-72 (Oct 18 2002) ISSN: 0021-9258 [Print] United States
• PMID: 12181316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Polyamines
• Proliferating Cell Nuclear Antigen
• 1-methylspermidine
• Spermine
• alpha-Amylases
• Zinc
• Spermidine

Topics

• Animals
• Animals, Genetically Modified
• Immunohistochemistry
• Liver (metabolism, pathology, physiology)
• Mice
• Pancreatitis (prevention & control)
• Polyamines (chemistry, metabolism, pharmacology)
• Proliferating Cell Nuclear Antigen (metabolism)
• Protein Binding
• Rats
• Regeneration
• Spermidine (analogs & derivatives, metabolism, pharmacology)
• Spermine (metabolism)
• Time Factors
• Zinc (metabolism, pharmacology)
• alpha-Amylases (blood)