Studies of the Pancreatotoxicity of 1-cyano-2-hydroxy-3-butene

Maher, Maurica (1991) Studies of the Pancreatotoxicity of 1-cyano-2-hydroxy-3-butene. Masters thesis, Memorial University of Newfoundland.

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Abstract

A racemic mixture of (R)- and (S)-1-cyano-2-hydroxy-3-butene (CHB) was synthesized using 1,3-butadiene as a starting compound. The effects of CHB on pancreatic non-protein thiol and glutathione S-transferase activity were investigated in adult male rats when administered orally in olive oil at a dose of 200 mg/kg. At 4 hours after dosing, pancreatic non-protein thiol content was depleted but rebounded at 24 hours to 3 times control values. At 120 hours after dosing, pancreatic non-protein thiol levels were still elevated over control levels. Hepatic non-protein thiol levels were greater than control levels at 4 hours after dosing, but were not significantly different from control values at 24 and 120 hours after dosing. The pattern of pancreatic non-protein thiol changes with synthetic CHB resembles that reported with the natural (S)- isomer of CHB. -- Glutathione S-transferase activity was decreased at 4 hours following CHB treatment in the rat pancreas, and elevated at 24 hours. Hepatic glutathione S-transferase activity was not altered by CHB treatment. -- The effect of increasing intraduodenal doses of CHB (25-200 mg/kg) on rat pancreatic juice secretion and bile secretion was investigated in conscious rats. CHB was administered intraduodenally and caused a stimulation in pancreatic juice secretion followed by a return to control values at the lower doses. At higher doses, CHB causes the same early stimulation, but is followed by a depression of pancreatic juice flow. All doses of CHB administered resulted in a dose-dependent decrease of protein concentration in pancreatic juice. -- CHB caused the pancreata of treated rats to become oedematous, a condition also seen in certain forms of acute pancreatitis. The severity of the oedema was dose-dependent and could be visually detected. The exudate collected from these pancreata had protein concentrations comparable to plasma. -- Radioactive CHB ([¹⁴C]) was synthesized and administered to rats intraduodenally that were also fitted with biliary fistulae. CHB was found to be excreted over 8 hours in the bile and urine, with higher amounts excreted in the urine. Little [¹⁴C] was detected in the pancreas and kidneys, but did accumulate in the adipose tissue (7.7%) and in the liver (5.5%). -- These results indicate that synthetic CHB is a powerful and selective pancreatotoxin and the present data are not incompatible with a glutathione-mediated mechanism, as is known to occur with other unsaturated nitriles.

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