Genetic predisposition to adverse consequences of anti–cholinesterases in ‘atypical’ BCHE carriers

Normal butyrylcholinesterase (BuChE)1, but not several of its common genetic variants2, serves as a scavenger for certain anti–cholinesterases (anti–ChEs). Consideration of this phenomenon becomes urgent in view of the large–scale prophylactic use of the anti–ChE, pyridostigmine, during the 1991 Persian Gulf War, in anticipation of nerve gas attack3 and of the anti–ChE, tacrine, for improving residual cholinergic neurotransmission in Alzheimer's disease patients4. Adverse symptoms were reported for subjects in both groups, but have not been attributed to specific causes4,5. Here, we report on an Israeli soldier, homozygous for ‘atypical’ BuChE, who suffered severe symptoms following pyridostigmine prophylaxis during the Persian Gulf War. His serum BuChE and recombinant ‘atypical’ BuChE (ref. 6) were far less sensitive than normal BuChE to inhibition by pyridostigmine and several other carbamate anti–ChEs. Moreover, atypical BuChE demonstrated 1/200th the affinity for tacrine of normal BuChE or the related enzyme acetylcholinesterase (AChE). Genetic differences among BuChE variants may thus explain at least some of the adverse responses to anti–ChE therapies.