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α-Methylspermidine protects against carbon tetrachloride-induced hepatic and pancreatic damage

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Abstract

The role of polyamines in carbon tetrachloride (CCl4)-induced organ injury was studied in syngenic rats and transgenic rats with activated polyamine catabolism. In syngenic rats, administration of CCl4 resulted in the induction of hepatic spermidine/spermine N 1-acetyltransferase (SSAT), accumulation of putrescine, reduction in spermine level and appearance of moderate hepatic injury within 24 h. Upon treatment with CCl4, transgenic rats overexpressing SSAT displayed induction of both hepatic and pancreatic SSAT, with subsequent accumulation of putrescine and decrease of both spermidine and spermine pools. Administration of CCl4 in SSAT transgenic rats induced not only massive hepatic injury, but also severe acute necrotizing pancreatitis. Pretreatment of the animals with catabolically stable functional polyamine mimetic, α-methylspermidine (MeSpd) prevented pancreatic and hepatic injury in SSAT rats and markedly reduced liver damage in syngenic animals. As assessed by immunostaining of proliferating cell nuclear antigen, MeSpd increased the amount of regenerating hepatocytes in both genotypes. These results show that CCl4 induces hepatic and pancreatic polyamine catabolism, and the extent of organ damage correlates with the degree of polyamine depletion. Furthermore, MeSpd protects against CCl4-induced hepatic and pancreatic damage and promotes tissue regeneration.

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Abbreviations

CCl4 :

Carbon tetrachloride

DFMO:

α-Difluoromethylornithine

IL:

Interleukin

ICAM-1:

Intracellular cell adhesion molecule-1

Me2Spm:

α,ω-Bismethylspermine

MeSpd:

α-Methylspermidine

ODC:

Ornithine decarboxylase

SSAT:

Spermidine/spermine N 1-acetyltransferase

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

The authors thank Mrs Tuula Reponen, Mrs Sisko Juutinen and Mrs Anne Karppinen for skillful technical assistance.

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Authors and Affiliations

  1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio, PL 1627, 70211, Kuopio, Finland

    Mervi T. Hyvönen, Riitta Sinervirta, Tuomo A. Keinänen & Leena Alhonen

  2. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

    Nikolay Grigorenko & Alex R. Khomutov

  3. Laboratory of Chemistry, Department of Biosciences, Biocenter Kuopio, University of Kuopio, Kuopio, Finland

    Jouko Vepsäläinen

Authors
  1. Mervi T. Hyvönen
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  2. Riitta Sinervirta
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  3. Nikolay Grigorenko
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  4. Alex R. Khomutov
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  5. Jouko Vepsäläinen
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  6. Tuomo A. Keinänen
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  7. Leena Alhonen
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Correspondence to Mervi T. Hyvönen.

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Hyvönen, M.T., Sinervirta, R., Grigorenko, N. et al. α-Methylspermidine protects against carbon tetrachloride-induced hepatic and pancreatic damage. Amino Acids 38, 575–581 (2010). https://doi.org/10.1007/s00726-009-0418-5

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  • DOI: https://doi.org/10.1007/s00726-009-0418-5

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