General and selective inhibition of pancreatic enzyme discharge using a proteinase inhibitor (FOY-305).
The guanidino acid esters (FOY, FOY-305) represent a new class of potent proteinase inhibitors and are thought to have a beneficial effect on the course of acute pancreatitis. Because of their structure and low molecular size they might enter cells and interfere with cellular processes. To test this possibility in the case of the exocrine pancreas a series of in vivo and in vitro studies was carried out to analyse intracellular transport and discharge of pancreatic enzymes in the presence of FOY-305. The infusion of FOY-305 to conscious rats led to a transient inhibition of protein and enzyme discharge from the cannulated pancreas accompanied by lower serum enzyme levels and increased enzyme content in the pancreas. An identical inhibition of discharge of newly synthesized proteins was observed in vitro in the presence of 1 microM FOY-305. The analysis of the release of individual enzymes using separation on two-dimensional gels showed a pronounced inhibition of mainly the release of acidic proteins. FOY-305 not only interfered with discharge of serine proteinases (trypsinogen, chymotrypsinogen, proelastase) but also with procarboxypeptidases and lipase. It was concluded that FOY-305 enters the acinar cell and due to an unspecific binding to acidic proteins interferes with the intracellular transport of individual enzyme proteins during their passage through the membrane-bound cellular compartments. This charge-dependent effect is independent of the inhibitory effect on enzymatic activity of serine proteinases.
D000681:Amylases / Q000037:antagonists & inhibitors; D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D043422:Carboxypeptidases A; D002919:Chymotrypsinogen / Q000037:antagonists & inhibitors; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014362:Trypsinogen / Q000037:antagonists & inhibitors
D004792:Enzyme Precursors; D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; C034532:camostat; D016670:Gabexate; D014362:Trypsinogen; D002919:Chymotrypsinogen; D008049:Lipase; D000681:Amylases; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; C022443:proelastase; D010196:Pancreatic Elastase