Separation of the toxic and glutathione-enhancing effects of the naturally occurring nitrile, cyanohydroxybutene

Cyanohydroxybutene (CHB) is reported to be hepatotoxic in male Fischer 344 rats at an oral dose of 300 mg/kg and, while no longer hepatotoxic, pancreatotoxic at 200 mg/kg. In addition, the 200 mg/kg dose causes a persistent elevation in hepatic and pancreatic glutathione (GSH). This study was conducted to determine if smaller doses of CHB could cause GSH elevation in the absence of toxicity. A single oral dose of 100 mg/kg or multiple lower doses (50 mg/kg daily for 3 days or 30 mg/kg for 6 days) caused a significant and persistent increase in pancreatic GSH, although hepatic levels were unchanged. Ten milligrams per kilogram, even daily for 24 days, was without effect on hepatic or pancreatic GSH. Neither a single oral dose of 100 mg/kg nor multiple lower doses were associated with toxicity. However, when either 100 or 50 mg/kg were administered intravenously, pancreatic apoptosis was observed. In animals dosed with 100 mg/kg iv, mixed histiocytic and suppurative inflammation and frank pancreatic necrosis also developed and were associated with elevated plasma lipase and amylase. The animals receiving CHB intravenously also exhibited elevated GSH levels in both pancreas and liver. This study shows that oral doses between 30 and 100 mg CHB/kg can be used to elevate GSH levels without any pancreatotoxicity. However, a single 50 mg CHB/kg dose given intravenously causes apoptosis, while 100 mg/kg causes severe pancreatotoxicity with necrosis.