Effects of S-adenosyl-1,8-diamino-3-thiooctane on polyamine metabolism.
Exposure of mammalian cells (transformed mouse fibroblasts or rat hepatoma cells) to S-adenosyl-1,8-diamino-3-thiooctane produced profound changes in the intracellular polyamine content. Putrescine was increased and spermidine was decreased, consistent with the inhibition of spermidine synthase by this compound, which is a potent and specific "transition-state analogue inhibitor" of the isolated enzyme in vitro. The spermine content of the cells was increased by exposure to this drug presumably since spermine synthase was able to use a greater proportion of the available decarboxylated S-adenosylmethionine when spermidine synthase was inhibited. The decarboxylated S-adenosylmethionine content rose substantially because the activity of S-adenosylmethionine decarboxylase was increased in response to the decline in spermidine. These results indicate that S-adenosyl-1,8-diamino-3-thiooctane is taken up by mammalian cells and is an effective inhibitor of spermidine synthase in vivo and that S-adenosylmethionine decarboxylase is regulated by the content of spermidine, but not of spermine. The growth of SV-3T3 cells was substantially reduced in the presence of S-adenosyl-1,8-diamino-3-thiooctane at concentrations of 50 microM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM alpha-(difluoromethyl)ornithine and 50 microM S-adenosyl-1,8-diamino-3-thiooctane, the content of all polyamines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D011700:Putrescine / Q000378:metabolism*; D051381:Rats; D013539:Simian virus 40; D013095:Spermidine / Q000378:metabolism*; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors; D013096:Spermine / Q000378:metabolism*
D013096:Spermine; C027548:S-adenosyl-3-thio-1,8-diaminooctane; D011436:Spermidine Synthase; D000241:Adenosine; D013095:Spermidine; D011700:Putrescine