Interaction of cycloheximide and diisopropylphosphorofluoridate (DFP) during subchronic administration in rat

Male Sprague-Dawley rats daily treated with DFP (0.5 mg/kg/day, sc) exhibited signs of cholinergic toxicity such as tremors and muscle fasciculations between Days 3 and 5 comparable to those observed 15 min after a single acute signs-producing dose (1.5 mg/kg, sc). Further administration of DFP (0.5 mg/kg/day, sc) for 6-14 days led to tolerance development as evidenced by disappearance of the described toxicity signs. The protein synthesis inhibitor cycloheximide, when given in a nontoxic dose (0.5 mg/kg/day, sc) 1 hr before DFP (0.5 mg/kg/day, sc) administration, potentiated the DFP toxicity and rats died after the fifth injection. DFP-tolerant rats developed toxicity signs when subsequently treated with cycloheximide (0.5 mg/kg/day, sc) and DFP (0.5 mg/kg/day, sc). Each drug when given alone for 4 days caused 30-50% reduction of [14C]valine uptake in vivo into the free amino acids pool as well as its incorporation into proteins of brain and skeletal muscles. A combination of these drugs caused a significantly greater inhibitory effect on [14C]valine incorporation into proteins. Cycloheximide (0.5 mg/kg/day, sc) administered for 4 days did not significantly alter the levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), or carboxylesterase (CarbE) activities but potentiated the DFP-induced inhibition of the activities of these enzymes. It is concluded that the cycloheximide pretreatment potentiates DFP toxicity by a mechanism that is related to inhibition of the synthesis of proteins such as AChE, BuChE, and CarbE.