Metabolic stability of alpha-methylated polyamine derivatives and their use as substitutes for the natural polyamines |
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Authors: | Järvinen Aki Grigorenko Nikolay Khomutov Alex R Hyvönen Mervi T Uimari Anne Vepsäläinen Jouko Sinervirta Riitta Keinänen Tuomo A Vujcic Slavoljub Alhonen Leena Porter Carl W Jänne Juhani |
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Institution: | A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland. |
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Abstract: | Metabolically stable polyamine derivatives may serve as useful surrogates for the natural polyamines in studies aimed to elucidate the functions of individual polyamines. Here we studied the metabolic stability of alpha-methylspermidine, alpha-methylspermine, and bis-alpha-methylspermine, which all have been reported to fulfill many of the putative physiological functions of the natural polyamines. In vivo studies were performed with the transgenic rats overexpressing spermidine/spermine N(1)-acetyltransferase. alpha-Methylspermidine effectively accumulated in the liver and did not appear to undergo any further metabolism. On the other hand, alpha-methylspermine was readily converted to alpha-methylspermidine and spermidine; similarly, bis-alpha-methylspermine was converted to alpha-methylspermidine to some extent, both conversions being inhibited by the polyamine oxidase inhibitor N(1), N(2)-bis(2,3-butadienyl)-1,4-butanediamine. Furthermore, we used recombinant polyamine oxidase, spermidine/spermine N(1)-acetyltransferase, and the recently discovered spermine oxidase in the kinetic studies. In vitro studies confirmed that methylation did not protect spermine analogs from degradation, whereas the spermidine analog was stable. Both alpha-methylspermidine and bis-alpha-methylspermine overcame the proliferative block of early liver regeneration in transgenic rats and reversed the cytostasis induced by an inhibition of ornithine decarboxylase in cultured fetal fibroblasts. |
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