Digestive enzymes are released in inactive forms called zymogens. This is necessary to prevent the digestive enzymes from digesting the cells that produce them. In a zymogen, a peptide blocks the active site of the enzyme. Cleaving off this peptide activates the enzyme.
The peptidase in the stomach is pepsin. Pepsin works
optimally in the acidic environment of the stomach, being active
at pH 2-3, but becoming inactivated when the pH is above 5. The chief
cells at the base of the gastric glands secrete the zymogen,
which is called pepsinogen. Activation of pepsinogen
starts when hydrocholoric acid (HCl), which is secreted by
the parietal cells partially activates pepsinogen
(pepsinogen* in figure). This partially active enzyme then cleaves
the peptide from other pepsinogen molecules to form active
Pancreatic zymogens are normally only activated after they reach the small intestine. A brush border enzyme, enterokinase, cleaves a peptide from trypsinogen, forming the active enzyme trypsin. Trypsin then activates the other enzymes.
A dangerous situation occurs if there is inappropriate formation of trypsin in the pancreas. This can cause pancreatitis, where trypsin digests pancreatic tissue and triggers an inflammatory response. Acinar cells synthesize and secrete a trypsin inhibitor that acts as a safeguard against trypsin activation within the pancreas. Another protective mechanism is that trypsin has a mechanisms of autolysis (self-digestion). Genetic mutations that decrease the activity of the pancreatic trypsin inhibitor increase the risk for pancreatitis, as do mutations that affect trypsinogen so that it is more likely to become prematurely activated or is resistant to autolysis.
A further important mechanism to protect against inappropriate activation of trypsin and pancreatitis is fluid secretion by duct cells to flush zymogens (or active enzymes) out of the pancreas and into the duodenum. Blockage of the pancreatic duct (for instance, by a gallstone) will prevent flow out of the pancreas and can be a cause of acute pancreatitis. Fluid secretion in the pancreas depends upon the chloride channel CFTR (as does fluid secretion in the lungs and small intestine). Patients with mutations in the CFTR gene (which causes cystic fibrosis) have an increased risk for the development of pancreatitis.
Two other factors that increase the risk for the development of
pancreatitis are excessive alcohol consumption and
hyperlipidemia. Alcohol and fatty acids cause inappropriate
intracellular activation of trypsin via mechanisms that are still