A polyamine analogue prevents acute pancreatitis and restores early liver regeneration in transgenic rats with activated polyamine catabolism.
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.
A.I. Virtanen Institute for Molecular Sciences and the Department of Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Tiina-Liisa
TL
Rasanen
Leena
L
Alhonen
Riitta
R
Sinervirta
Tuomo
T
Keinanen
Karl-Heinz
KH
Herzig
Suvikki
S
Suppola
Alex R
AR
Khomutov
Jouko
J
Vepsalainen
Juhani
J
Janne
D000818:Animals; D030801:Animals, Genetically Modified; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051379:Mice; D010195:Pancreatitis / Q000517:prevention & control*; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012038:Regeneration; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013096:Spermine / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology; D000516:alpha-Amylases / Q000097:blood
D011073:Polyamines; D018809:Proliferating Cell Nuclear Antigen; C073193:1-methylspermidine; D013096:Spermine; D000516:alpha-Amylases; D015032:Zinc; D013095:Spermidine