Cerulein-induced pancreatic cysteine depletion: prevention does not diminish acute pancreatitis in the mouse.

BACKGROUND/AIMS: Induction of acute necrotizing pancreatitis with cerulein causes profound pancreatic glutathione depletion in the mouse. Because cysteine availability can be rate-limiting for glutathione synthesis, the pancreatic content of cysteine during cerulein treatment was measured and the potential benefit of augmenting pancreatic cysteine was determined.

METHODS

Female Swiss-Webster mice were treated with cerulein with and without simultaneous administration of the cysteine prodrug, L-2-oxothiazolidine 4-carboxylic acid. Pancreatic cysteine and glutathione content were measured, and serum amylase levels and pancreatic histology were assessed.

RESULTS

Pancreatic cysteine content decreased to 42% of normal after 4 hours of cerulein treatment. L-2-oxothiazolidine 4-carboxylic acid more than doubled pancreatic cysteine content at 4 hours and prevented pancreatic cysteine depletion when administered with cerulein. Cerulein caused pancreatic glutathione depletion despite this normalization of cysteine. Moreover, the biochemical and histological evidence of cerulein-induced pancreatitis was unaltered by preventing cysteine depletion.

CONCLUSIONS

Pancreatic cysteine is depleted during induction of acute pancreatitis with cerulein in parallel with depletion of pancreatic glutathione. Because preventing pancreatic cysteine depletion with L-2-oxothiazolidine 4-carboxylic acid did not prevent glutathione loss, causes of pancreatic glutathione depletion other than insufficiency of this critical precursor must also play an important role in cerulein-induced glutathione depletion.