Genetic Predisposition for Variable Response to Anticholinesterase Therapy Anticipated in Carriers of the Butyrylcholinesterase “Atypical” Mutation

Abstract

Anticholinesterases were recently approved for treating patients suffering from Alzheimer’s disease (AD) in an attempt to balance their cholinergic system. These drugs are targeted at acetylcholinesterase (AChE) but also inhibit butyrylcholinesterase (BuChE), known for its numerous genetic variants. The most common of these is the “atypical” phenotype created through a replacement of Asp70 by Gly (D70G) due to a point mutation. The “atypical” enzyme causes prolonged postanesthesia apnea following succinylcholine administration for muscle relaxation and displays a considerably reduced sensitivity to various other inhibitors. The allelic frequency of “atypical” BuChE was studied in different populations and revealed distinct patterns particular to various ethnic groups. Recently, a relatively high allelic frequency of 0.06 was found in a population of Georgian Jews, differing by up to 4-fold from the incidence in other populations (Ehrlich et al., Genomics, in press). This implies that in groups of AD patients from diverse ethnic origins, a significant fraction of carriers of at least one allele of this mutation should be expected. To predict their responsiveness to anticholinesterase treatment, we examined the susceptibility of AChE, as compared to that of BuChE and the “atypical” BuChE variant, towards several anticholinesterases in use for AD treatment. IC50 values and rate constants reflecting inhibitor susceptibilities were calculated for various recombinant human cholinesterases produced in Xenopus oocytes and immobilized on microtiter plates through selective monoclonal antibodies. The reversible amino acridinium compound Tacrine, currently in use for AD therapy, displayed a 300-fold higher IC50 value for the “atypical” enzyme than for BuChE (1mM BtCh as substrate). Pseudo first order rate constants for inhibition of BuChEs by the carbamates heptyl-physostigmine (0.139 min−1, lOnM inhibitor), physostigmine (0.3 min−1, 1 μM inhib.) and SNZ-ENA713 (0.139 min−1, 10 μM inhib.) were found to be higher than or equal to those of AChE, suggesting that BuChE serves as a second primary target for these drugs. Moreover, the “atypical” variant of BuChE displayed considerably slower inactivation rates to these drugs (0.01 min−1, 0.025 min−1, and 0.01 min−1, respectively) as compared with the wild type BuChE. These findings predict that carriers of the D70G BuChE mutation would vary from other patients in their susceptibility to the above drugs, which potentially contributes to the wide variability of responses observed in clinical trials. Screening patients for D70G carriers should therefore precede anticholinesterase treatment.