INHIBITION OF HUMAN PANCREATIC PROTEINASES BY MUCUS PROTEINASE-INHIBITOR, EGLIN-C AND APROTININ

The kinetic investigation of the inhibition of human pancreatic trypsi n 1, trypsin 2 and chymotrypsin A by mucus proteinase inhibitor, eglin c and aprotinin reveals that (i) the first protein is a potent inhibi tor of chymotrypsin A (k(ass.) = 1.4 x 10(6) M(-1).s(-1), K-i = 71 pM) but forms loose complexes with trypsin 1 (K-i = 0.5 mu M) and trypsin 2 (K-i = 18 nM), (ii) eglin c does not inhibit the two trypsins but f orms a tight complex with chymotrypsin A (k(ass.) = 3.3 x 10(6) M(-1). s(-1), K-i < 0.1 nM) and (iii) aprotinin is a potent inhibitor of tryp sin 1 (k(ass.) = 1 x 10(5) M(-1).s(-1), K-i < 0.2 nM) and trypsin 2 (k (ass.) = 2.4 x 10(5) M(-1).s(-1), K-i < 1 nM) but forms a loose comple x with chymotrypsin A (K-i = 0.17 mu M). These data, together with tho se published previously on human pancreatic elastase, suggest that a c ocktail of aprotinin + eglin c might be a better intensive-care drug f or acute pancreatitis than aprotinin alone, because it will efficientl y inhibit all four human pancreatic proteinases. On the other hand, hu man gastric juice inactivates mucus proteinase inhibitor by pepsin-med iated cleavage. This indicates that the fraction of mucus proteinase i nhibitor 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 pa tients.