engleski

Human cholinesterases inhibition with isoproterenol and its dicarbamate ester

Introduction. Isoproterenol (4-[1-hydroxy-2-(1-methylethylamino) ethyl] benzene-1, 2-diol), a sympathomimetic beta adrenergic receptor agonist used to treat asthma, and its dimethylcarbamate ester were studied as inhibitors of human erythrocytes acetylcholinesterase (AChE ; EC 3.1.1.7) and plasma butyrylcholinesterase (BChE ; EC 3.1.1.8). The aim was to determine dissociation or rate constants and to compare the selectivity of the two related enzymes as well as of native BChE variants (U, A and F). Results. Homozygous usual BChE (UU) has the highest affinity for isoproterenol (i.e. the lowest dissociation constant, Ki=0.47 mM) while AChE has the lowest affinity (Ki=2.5 mM). The dissociation constants for the homozygous atypical BChE (AA), fluoride-resistant (FF) and heterozygote UA were 1.6, 0.99 and 0.72 mM, respectively. Dimethylcarbamate ester of isoproterenol inhibited usual BChE 90 times faster than AChE, while the inhibition rate constants of BChE variants ranged from 0.021 min-1  M-1 for AA to 0.20 min-1  M-1 for UU BChE. Conclusions. Both inhibitors are more potent for BChE than AChE, but carbamoylation by dimethylcarbamate of isoprotenerol is more selective. Since isoprotenerol is the leaving group of the ester and a product of cholinesteraseres carbomoylation, the ester could be used as a prodrug because slow hydrolysis of dimethylcarbamate of isoproterenol by plasma BChE could ensure a slow release of isoproterenol in the organism.

AChE; BChE; phenotypes; isoproterenol; dicarbamate ester

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