Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine͞spermine N 1 -acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N 1 -acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N 1 ,N 2 -bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N 1 ,N 11 -diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N 1 ,N 11 -diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.I ntracellular polyamine levels are tightly maintained by a number of mechanisms, suggesting their importance for cell function. This polyamine homeostasis is controlled by their biosynthesis, interconversion, catabolism, secretion, and uptake. Polyamine biosynthesis is regulated by the activities of ornithine and S-adenosylmethionine decarboxylases. Overexpression of ornithine decarboxylase in transgenic rodents affected spermatogenesis (1, 2), rendered animals more resistant to chemically or electrically induced seizure activity (3) and to ischemic insults (4), and enhanced skin papilloma formation (5). However, the activation of polyamine biosynthesis caused by overexpression of ornithine decarboxylase did not result in enhanced accumulation of the higher polyamines spermidine and spermine. Polyamine catabolism is controlled by the activity of spermidine͞spermine N 1 -acetyltransferase (SSAT; refs. 6 and 7). The acetylated products are oxidized further by the polyamine oxidase (PAO) to spermidine and putrescine. We recently generated transgenic mouse lines with ...