Pancreatic Exocrine Secretion Is Blocked by Inhibitors of Methylation

Abstract

A number of early experiments suggested a relationship between methyl group metabolism and the exocrine secretion of the pancreas. These included nutritional studies showing that ethionine, the ethyl analog of methionine which inhibits cellular methylation reactions, is a specific pancreatic toxin. Other studies indicated that protein carboxymethylation might be involved. We now show thatin vivoethionine inhibits amylase secretion from freshly isolated rat pancreatic acini, whilein vitroethionine inhibits amylase secretion from the AR42J pancreatic cell line.S-Adenosylhomocysteine (SAH) is a product inhibitor of all methyltransferase reactions involvingS-adenosylmethionine (SAM), and treatments that elevate cellular levels of SAH such as inhibition ofS-adenosylhomocysteine hydrolase and thein vitroaddition of adenosine and homocysteine result in the inhibition of amylase secretion in both isolated pancreatic acini and AR42J cells. Measurement of SAM and SAH levels in AR42J cells shows that inhibition of secretion is more closely related to elevation of SAH levels than to a decrease in the SAM/SAH ratio. Small G-proteins are carboxymethylated on the C-terminal prenylated cysteine and inhibitors of membrane-associated prenylcysteine methyltransferase,N-acetylfarnesylcysteine,N-acetylgeranylgeranylcysteine, and farnesylthioacetic acid (FTA), block secretion in AR42J cells.N-Acetylgeranylcysteine is not an inhibitor of the methyltransferase and does not inhibit amylase secretion. FTA inhibits membrane-associated prenylcysteine methyltransferase from AR42J cells with aKiin the 45–69 μmrange. These results suggest that a methylation event is needed for pancreatic exocrine secretion which may be the reversible methylation of a G-protein involved in signal transduction or membrane trafficking.