TRANSGENIC MICE OVER-PRODUCING PUTRESCINE IN THEIR TISSUES DO NOT CONVERT THE DIAMINE INTO HIGHER POLYAMINES

We recently described a transgenic mouse line over-expressing the huma n ornithine decarboxylase gene virtually in all tissues. Despite strik ingly elevated tissue putrescine concentrations, no or minimal changes were found in the levels of the higher polyamines spermidine and sper mine. We have now extended these studies by further increasing tissue putrescine with the aid of 5-fluoromethylornithine, a specific inhibit or of ornithine transaminase and hence the catabolism Of L-ornithine. As a result of the treatment with the latter drug, the concentration o f putrescine was further increased by a factor of 2-3 without any chan ges in the concentrations of spermidine and spermine. In the testis of transgenic mice treated with 5-fluoromethylornithine, the concentrati on of putrescine was nearly 60 times that in non-transgenic untreated animals, yet the concentration of spermidine was only 1.5-fold higher. A similar small increase in brain spermidine was accompanied by a 40- fold elevation in the concentration of putrescine. The apparent blocka de between putrescine and spermidine was in all likelihood not attribu table to an inhibition of S-adenosylmethionine decarboxylase, the rate -controlling enzyme in the biosynthesis of spermidine and spermine. Ou r results are more compatible with the view that in non-dividing adult tissues putrescine is sequestered through some unknown mechanisms in a way that makes it unavailable for the synthesis of the higher polyam ines.