IMPORTANCE OF INTRACELLULAR S-ADENOSYLMETHIONINE DECARBOXYLASE ACTIVITY FOR THE REGULATION OF CAMOSTATE-INDUCED PANCREATIC POLYAMINE METABOLISM AND GROWTH - IN-VIVO EFFECT OF 2 NOVEL S-ADENOSYLMETHIONINE DECARBOXYLASE INHIBITORS

The present study was designed to investigate the inhibitory potency o f the two novel S-adenosylmethionine decarboxylase (SAM-DC) inhibitors MDL 73811 and CGP 48664 on the camostate-induced pancreatic polyamine metabolism and especially intracellular spermidine accumulation as we ll as pancreatic growth in vivo, Male Wistar rats (180 g) were either treated with (1) the synthetic trypsin inhibitor camostate (100 mg/kg b.w. orally twice daily), (2) camostate + MDL 73811 (100 mg/kg b.w.i.p . twice daily), (3) camostate + CGP 48664 (5 mg/kg b.w.i.p. once daily ) or (4) saline as controls, Animals (5-9 pet group) were sacrificed a fter 1, 2 and 5 days of treatment, MDL 73811 caused a long-lasting (>9 5%; p < 0.005) inhibition of SAM-DC followed by a significant (p < 0.0 05) increase in ornithine decarboxylase and putrescine, while spermine was decreased (p < 0.005). In contrast to MDL 73811, CGP 48664 had li ttle effect in vivo. Despite potent inhibition of SAM-DC camostate-sti mulated intracellular spermidine accumulation was not prevented by the simultaneous administration of MDL 73811, Consequently organ growth w as not affected either, Since de novo synthesis of spermidine was effe ctively inhibited by MDL 73811, counterregulatory mechanisms (i.e. int erconversion pathway, extracellular uptake) had to step in to maintain the intracellular balance of spermidine, The present data support the general concept of the importance of intracellular spermidine accumul ation for the maintenance of pancreatic growth in vivo.