Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Polyamines are required for optimal growth and function of cells. Regulatio n of their cellular homeostasis is therefore tightly controlled. The key re gulatory enzyme for polyamine catabolism is the spermidine/spermine N-1-ace tyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the ph ysiological function SSAT, we generated a transgenic rat line overexpressin g the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreat ic SSAT, overaccumulation of putrescine, and appearance of N-1-acetylspermi dine with extensive depletion of spermidine and spermine in transgenic anim als. The activation of pancreatic polyamine catabolism resulted in acute pa ncreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic: polyamine pools, nor did it induce pancreatitis. Acetylated pol yamines. products of the SSAT-catalyzed reaction, are metabolized further b y the polyamine oxidase (PAO) generating hydrogen peroxide. which might cau se or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N-1,N-2-bis(2,3-butadienyl)-1,4-butanedia mine]. however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N-1,N-11-diethylnorspermine red uced pancreatic polyamines levels only moderately and without signs of orga n inflammation. In contrast, the combination of N-1,N-11-diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of p ancreatic 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 pancr eatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.