Inhibition of human pancreatic proteinases by mucus proteinase inhibitor, eglin c and aprotinin

Abstract

The kinetic investigation of the inhibition of human pancreatic trypsin 1, trypsin 2 and chymotrypsin A by mucus proteinase inhibitor, eglin c and aprotinin reveals that (i) the first protein is a potent inhibitor of chymotrypsin A (kass. = 1.4×106 M-1·s-1, Ki = 71 pM) but forms loose complexes with trypsin 1 (Ki = 0.5 μM) and trypsin 2 (Ki = 18 nM), (ii) eglin c does not inhibit the two trypsins but forms a tight complex with chymotrypsin A (kass. = 3.3×106 M-1·s-1, Ki < 0.1 nM) and (iii) aprotinin is a potent inhibitor of trypsin 1 (kass.=1×105 M-1·s-1, Ki<0.2 nM) and trypsin 2 (kass. = 2.4×105 M-1·s-1, Ki < 1 nM) but forms a loose complex with chymotrypsin A (Ki = 0.17 μM). These data, together with those published previously on human pancreatic elastase, suggest that a cocktail of aprotinin+eglin c might be a better intensive-care drug for acute pancreatitis than aprotinin alone, because it will efficiently inhibit all four human pancreatic proteinases. On the other hand, human gastric juice inactivates mucus proteinase inhibitor by pepsin-mediated cleavage. This indicates that the fraction of mucus proteinase inhibitor that reaches the stomach following aerosol delivery to cystic fibrosis patients does not reach the duodenum in an active form and, therefore, does not aggravate the pancreatic insufficiency of these patients.