Interaction of Human Butyrylcholinesterase Variants with Bambuterol and Terbutaline

Abstract

Bambuterol, a dimethylcarbamate, carbamoylates butyrylcholinesterase (BChE; EC 3.1.1.8). The carbamoylated enzyme is not very stable and the final product of the two-step hydrolysis is a bronchodilator drug, terbutaline (1-(3,5-dihydroxyphenyl)-2-t-butylamino-ethanol sulphate). Both bambuterol and terbutaline inhibit BChE, but their affinities differ in human serum BChE variants (U, A, F, K and S) due to their positive charge. Bambuterol inhibition rate constants for the homozygous usual (UU), Kalow (KK), fluoride-resistant (FF) or atypical (AA) variant ranged from 4.4 to 0.085min (-1)microM(-1). Terbutaline showed competitive reversible inhibition for all BChE variants. The dissociation constants for UU, FF and AA homozygotes were 0.18, 0.31 and 3.3 mM, respectively. The inhibition rate or dissociation constants for heterozygotes were distributed between the respective constants for the corresponding homozygotes. A 50-fold difference in inhibition between the UU and AA enzyme might affect terbutaline release in humans. The affinity of all studied BChE variants for terbutaline was low, which suggests that terbutaline originating from bambuterol hydrolysis should not affect the hydrolysis of bambuterol by BChE.

Stereoselective Inhibition of Human Butyrylcholinesterase by the Enantiomers of Bambuterol and Their Intermediates

“…The enantioselective time-and concentration-dependent inhibition mechanism obtained when BMB enantiomers were used as inhibitors is in agreement with previously reported findings and confirms the hydrolysis model (Fig. 1) previously proposed (Kovarik and Simeon-Rudolf, 2004;Gazi c et al, 2006). In fact, according to this model, the interaction between BMB and BChE results in a virtually irreversible complex formation, and this is consistent with the linear correlation between the pseudo-first-order rate constant (k obs ) and BMB concentration (Fig.…”

“…The kinetic parameters obtained were used to model the BChE inhibition caused by BMB without the contribution of MONO and to evaluate the effect of the enzyme inhibition on the production rate of TBT. The contribution of TBT to the inhibition of BChE was not investigated because its role at therapeutic plasma concentrations can be considered insignificant (Kovarik and Simeon-Rudolf, 2004). (racemic BMB hydrochloride,mol.…”

Cholinesterases: Structure, Role, and Inhibition

“…Osim prirodnog karbamata fizostigmina brojni sintetički karbamati imaju primjenu kao lijekovi. Tako se rivastigmin (Exelon ® ) rabi u terapiji miastenije gravis, bambuterol (Bambec ® ) predlijek je bronhodilatatora terbutalina i rabi se u terapiji astme, dok postotak inhibicije s Ro-02-0683 koristi u identifi kaciji prirodnih inačica ljudske BChE (78)(79)(80)(81). Sinteza ireverzibilnih inhibitora kolinesteraza razvijana je i u svrhu upotrebe ovih spojeva kao pesticida u kontroli nametnika u poljoprivrednoj proizvodnji (82).…”

“…Valja napomenuti da se kod ireverzibilnih inhibitora IC 50 odnosi na reverzibilni kompleks enzim-inhibitor i da daje informaciju o afi nitetu enzima prema inhibitoru, ali ne govori o brzini progresivne inhibicije. Jednim od vrlo selektivnih inhibitora kolinesteraza pokazao se i već spomenuti bambuterol koji mišju BChE inhibira 16.000 puta brže od mišje AChE, dok ljudsku BChE inhibira oko 10.000 puta brže od ljudske AChE, što ga svrstava u skupinu izrazito selektivnih inhibitora BChE (78,79,89).…”

Stereoselective inhibition of butyrylcholinesterase by enantiomers ofexo- andendo-2-norbornyl-N-n-butylcarbamates

“…The derivatives of physostigmine ( Figure 2) are also potential drugs for the treatment of AD 22,23 . Since rivastigmine 24 , bambuterol 25 , and physostigmine are carbamates, inhibition mechanisms of both AChE and BChE by carbamates may play important roles for the treatment of AD [19][20][21][22][23][24][25][26][27] . Carbaryl (1-naphthyl N-methylcarbamate, Sevin) (Figure 2), carbofuran (Furadan), propoxur (Baygon), and aldicarb (Temik) are carbamate pesticides that have activities against a broad range of insects and low mammalian toxicity 28 .…”