1. Carbenoxolone, in suspension at pH 4·0, inhibits swine pepsin A, and human pepsins 1, 3 and 5. Human pepsin 5 is the most readily inhibited, and human pepsin 1 the least.
2. Inhibition occurs by a process which is time-dependent, temperature-dependent and proportional to the quantity of carbenoxolone suspended.
3. Carbenoxolone, in solution at pH 7·4 and pH 8·0, inhibits the activation of the total pepsinogens of human gastric mucosal extracts and of the individual pepsinogens 1, 3 and 5. Pepsinogen 1 was the most readily inhibited, pepsinogen 5 the least.
4. Chymotrypsin was readily inhibited by carbenoxolone at pH 7·4 and 8·0. Trypsin was not inhibited at pH 7·4 but was inhibited, relatively weakly, at pH 8·0. Pronase was weakly inhibited at pH 7·4 and 8·0 but papain was weakly activated.
5. Carbenoxolone is therefore not a general enzyme inhibitor but shows specificity for enzymes (pepsins and chymotrypsin) which split proteins at the same bonds, rather than for enzymes with similar active centres (chymotrypsin and trypsin).
6. The results suggest that, in vivo, carbenoxolone might diminish peptic activity in three ways: by inactivating pepsinogens irreversibly in the mucosal cells or at some point before their activation to pepsins; by inhibiting pepsins irreversibly in the gastric lumen; and by binding pepsins in the lumen without destroying their activity but decreasing their effective concentration.
7. These results are compatible with the hypothesis that pepsins, and pepsin 1 particularly, are factors in the aetiology of peptic ulcer.