engleski

Bambuterol and terbutaline inhibition of human serum butyrylcholinesterase natural variants

Bambuterol (5-[2-(tert-butylamino)-1-hydroxyethyl]-m-phenylene-bis(di-methylcarbamate) hydrochloride), an oral bronchodilatator drug, is hydrolysed to active b2-adrenerigic agonist terbutaline (1-(3, 5-dihydroxyphenyl)-2-t-butylaminoethanol hydrochloride) by butyrylcholinesterase (BChE ; EC 3.1.1.8) in a two-step process. The aim of this study was to determine the difference in the sensitivity of human serum BChE variants (U, A, F, K and S) to bambuterol and terbutaline through their inhibition of homozygous usual (UU), atypical (AA), fluoride-resistant (FF), and Kalow (KK) phenotypes and of heterozygotes UA, UF, AF, UK, AK, and US. Bambuterol is a progressive inhibitor of BChE and rate constants were determined from the time course of inhibition of the phenotypes. Terbutaline is a reversible inhibitor of BChE and dissociation inhibition constants were determined from the degree of inhibition of propionylthiocholine hydrolysis by BChE. All measurements were done in 0.1 mM phosphate buffer, pH 7.4 at 25 °C by spectrophotometric method with DTNB as thiol reagent. The bambuterol inhibition rate constants for the homozygotes UU, KK, FF and AA were 4.4x106, 3.8x106, 9.5 x105 and 8.5x104 min-1M-1, respectively. Terbutaline competitively inhibited all BChE phenotypes and dissociation constants for the homozygotes UU, FF and AA were 0.18, 0.31 and 3.3 mM, respectively. Inhibition rate or dissociation constants for heterozygotes were distributed between the respective constants of corresponding homozygotes. As the affinity of any studied BChE variant for terbutaline was relatively low, terbutaline, originated from bambuterol hydrolysis, should not affect the BChE hydrolysis of bambuterol.

Bambuterol; terbutaline; inhibition; human butyrylcholinesterase

nije evidentirano