Importance of intracellular S-adenosylmethionine decarboxylase activity for the regulation of camostate-induced pancreatic polyamine metabolism and growth: in vivo effect of two novel S-adenosylmethionine decarboxylase inhibitors.
The present study was designed to investigate the inhibitory potency of 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 well as pancreatic growth in vivo. Male Wistar rats (180 g) were either treated with (1) the synthetic trypsin inhibitor camostate (200 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 per group) were sacrificed after 1, 2 and 5 days of treatment. MDL 73811 caused a long-lasting (> 95%; p < 0.005) inhibition of SAM-DC followed by a significant (p < 0.005) increase in ornithine decarboxylase and putrescine, while spermine was decreased (p < 0.005). In contrast to MDL 73811, CGP 48664 had little effect in vivo. Despite potent inhibition of SAM-DC camostate-stimulated intracellular spermidine accumulation was not prevented by the simultaneous administration of MDL 73811. Consequently organ growth was not affected either. Since de novo synthesis of spermidine was effectively inhibited by MDL 73811, counterregulatory mechanisms (i.e. interconversion 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 accumulation for the maintenance of pancreatic growth in vivo.
Löser
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1st Medical Department, Christian Albrechts University, Kiel, Germany.
Fitting
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Fölsch
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D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D003839:Deoxyadenosines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011073:Polyamines / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D000578:Amidines; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D004952:Esters; D006146:Guanidines; D007189:Indans; D011073:Polyamines; C034532:camostat; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D016670:Gabexate; C065859:MDL 73811; D012437:Adenosylmethionine Decarboxylase