Activation of zymogens within the pancreatic acinar cell is an early feature of acute pancreatitis. Supraphysiologic concentrations of cholecystokinin (CCK) cause intrapancreatic zymogen activation and pancreatitis. Supraphysiologic concentrations of CCK also cause zymogen activation in isolated pancreatic acini. This activation first occurs in a nonzymogen granule compartment that contains lysosomal markers. A low pH environment may also be needed for activation. To examine the ability of alcohols to sensitize the acinar cell to CCK, the conversion of zymogens to active enzymes in isolated acini was assayed. Alcohols, including 35 mmol/L ethanol, sensitized acini to CCK induced activation. The sensitization increased with chain length and was less in branched compared with unbranched alcohols. The relationship of alcohol's structure to sensitization may be related to the mechanism of sensitization.