Importance of various intracellular regulatory mechanisms of polyamine metabolism in camostate-induced pancreatic growth in rats.
Aim of the present study was to evaluate the relevance of various intracellular regulatory mechanisms of polyamine metabolism in normal and camostate (FOY 305)-induced pancreatic growth in rats. Furthermore it was investigated whether the simultaneous inhibition of the polyamine interconversion pathway by the potent polyamine oxidase inhibitor MDL-72527 together with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) is able to enhance and prolong the only initial and transient inhibitory effects of DFMO on camostate-induced pancreatic growth. Simultaneous administration of DFMO and MDL-72527 resulted in a significant inhibition of the camostate-induced increases in pancreatic putrescine, ODC and DNA over 5 days, while the initial significant inhibition of pancreatic weight, protein content, DNA-polymerase and especially spermidine was absent after 5 days and spermine as well as N1-acetylspermidine were even increased. Diamine oxidase (DAO) activity in pancreas is very low and the potent DAO inhibitor aminoguanidine failed to alter any of the measured parameters except DAO. Therefore, oxidative degradation of putrescine by DAO--which is essential in the gut--is irrelevant in the pancreas. Simultaneous inhibition of the pancreatic polyamine interconversion pathway extended the initial inhibitory effects of DFMO only slightly and failed to exert a potent long-lasting inhibitory effect on spermidine and pancreatic growth.
Löser
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Department of Internal Medicine, Christian Albrecht University of Kiel, FRG.
Fölsch
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D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D000518:Eflornithine / Q000494:pharmacology; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D009955:Ornithine Decarboxylase / Q000502:physiology; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D015317:Biogenic Polyamines; D004952:Esters; D006146:Guanidines; D065108:Ornithine Decarboxylase Inhibitors; D014361:Trypsin Inhibitors; C034532:camostat; C044445:MDL 72527; D016670:Gabexate; D006631:Amine Oxidase (Copper-Containing); D000587:Oxidoreductases Acting on CH-NH Group Donors; D009955:Ornithine Decarboxylase; C004479:pimagedine; D011700:Putrescine; D000518:Eflornithine