Inhibition of Polyamine Synthesis by α-Difluoromethylornithine and its Effects on Pancreatic Secretion and Growth in the Rat

Abstract

The role played by the polyamines in mediating the pancreatic growth and secretory responses to hormonal stimulation is uncertain. The effect of an inhibitor of ornithine decarboxylase (ODC), alpha-difluoromethylornithine (DFMO), on rat pancreatic protein secretion and synthesis and on growth in response to hormonal stimulation was therefore studied. Anesthetized rats were given an intravenous injection of DFMO (50, 100, or 150 mg/kg), followed by a 7-h continuous infusion (15, 25, or 35 mg/kg/h, respectively). After a basal 1-h period an intravenous infusion of 2.5 micrograms/kg/h of the cholecystokinin-like peptide Thr28Nle31CCK25-33 (CCK-LP) was added and continued for 6 h. The control rats received CCK-LP only. The ODC activity in the pancreas was markedly reduced by DFMO, but DFMO did not affect pancreatic juice volume or protein output. In another series conscious rats were given a continuous intravenous infusion of 2.5 micrograms/kg/h of CCK-LP for 8, 24, and 48 h or 5.0 micrograms/kg/h of secretin for 8 and 48 h, with or without DFMO (100 mg/kg as an injection initially and thereafter 25 mg/kg/h). The ODC activity and putrescine concentration in the pancreas were significantly reduced by DFMO at 8 and 24 h but not at 48 h. DFMO also significantly reduced the activities of RNA polymerase, DNA polymerase, and thymidine kinase at 24 h, but not at 48 h. The present study thus indicates that polyamines play a role in the initiation of the growth response to hormonal stimulation but does not support a similar dependence for early pancreatic protein synthetic and secretory responses.

Polyamines in Pancreatic Growth

“…It could be shown that neither CCK-LP stimu lated pancreatic volume nor enzyme secre tion could be inhibited by giving simulta neously DFMO [11]. Similar to the studies concerning pancreatic growth, the applica tion of DFMO was not able to reduce the polyamine concentrations under a critical level.…”

“…The initial and transient inhibitory effect of DFMO on stimulated polyamines has also been described by Haarstad et al [ 11 ]. If the pancreatic polyamine concentration can hardly be reduced though the rate-limiting enzyme ornithine decarboxylase is effec tively inhibited, several other sources apart a de novo synthesis of polyamines have to be considered in order to maintain or to in crease the level of putrescine and spermidine [2] (fig.…”

Importance of Various Intracellular Regulatory Mechanisms of Polyamine Metabolism in Camostate-lnduced Pancreatic Growth in Rats

“…While the important role of polyamine de novo synthe sis by ODC mainly during the induction of CCK-or camostate-induced pancreatic growth is well-defined [9,11,[13][14][15][16], nothing is known concerning the relevance of the various further intracellular regulatory mechanisms of the polyamine metabolism. The data of the present study clearly show three major findings.…”

“…The important role of the polyamine metabolism dur ing CCK or camostate-induced pancreatic growth was recently stressed by several authors [9,[11][12][13][14][15][16], In a for mer study we could clearly demonstrate the crucial role of polyamine de novo synthesis by ODC in CCK-and camostate-induced pancreatic growth mainly for the in duction of the trophic process [9,11]. Data concerning the role of further intracellular regulatory mechanisms of the polyamine metabolism during pancreatic growth are not available and especially the importance of the intercon version pathway as well as the oxidative degradation by amine oxidases remains to be determined.…”

Animal disease models generated by genetic engineering of polyamine metabolism

“…The role of the very high spermidine content in pancreas is not known, but it may be related to the extremely active protein synthesis going on in this particular tissue. The polyamines seem to be required for pancreatic growth and maturation [68], while their role in the exocrine function of the organ is less obvious [69].…”