Concurrent overexpression of ornithine decarboxylase and spermidine/spermine N-1-acetyltransferase further accelerates the catabolism of hepatic polyamines in transgenic mice

We have generated a hybrid transgenic mouse line overexpressing both ornith ine decarboxylase (ODC) and spermidine/spermine N-1-acetyltransferase (SSAT ) under the control of the mouse metallothionein (MT) I promoter. In compar ison with singly transgenic animals overexpressing SSAT, the doubly transge nic mice unexpectedly displayed much more striking signs of activated polya mine catabolism, as exemplified by a massive putrescine accumulation and an extreme reduction of hepatic spermidine and spermine pools. Interestingly, the profound depletion of the higher polyamines in the hybrid animals occu rred in the presence of strikingly high ODC activity and tremendous putresc ine accumulation. Polyamine catabolism in the doubly transgenic mice could be enhanced further by administration of zinc or the polyamine analogue N-1 ,N-11-diethylnorspermine. In tracer experiments with [C-14]spermidine we fo und that, in comparison with syngenic animals, both MT-ODC and MT-SSAT mice possessed an enhanced efflux mechanism for hepatic spermidine. In the MT-O DC animals this mechanism apparently operated in the absence of measurable SSAT activity. In the hybrid animals, spermidine efflux was stimulated furt her in comparison with the singly transgenic animals. In spite of a dramati c accumulation of putrescine and a profound reduction of the spermidine and spermine pools, only marginal changes were seen in the level of ODC antizy me. Even though the hybrid animals showed no liver or other organ-specific overt toxicity, except an early and permanent loss of hair, their life span was greatly reduced. These results can be understood from the perspective that catabolism is the overriding regulatory mechanism in the metabolism of the polyamines and that, even under conditions of severe depletion of sper midine and spermine, extremely high tissue pools of putrescine are not driv en further to replenish the pools of the higher polyamines.