Effect of butobendin on dopamine beta-hydroxylase in vitro.
It has been found that dopamine beta-hydroxylase (DBH) (E.C.1.14.17.1), a key enzyme in the multistep process of adrenaline formation, isolated from blood serum by fractionated salting out procedure, is an allosteric enzyme with a sigmoidal kinetics and positive cooperativity in binding of the substrate and effectors. Butobendin, a double ester of 2-aminobutanol and trimethoxybenzoic acid, a new interesting compound showing various pharmacological and metabolic properties, inhibits DBH activity stereospecifically, only in the configuration 2S,2'S, decreasing DBH Vmax. This noncompetitive inhibitory effect of butobendin was stronger than the feed-back DBH inhibition by adrenaline and noradrenaline or by quinidine used as a standard antiarrhythmic compound. At high butobendin concentration (1.55 microM) the DBH activity was stabilized at about 50% of initial activity. This indicates that tetrameric enzyme binds substrate to half-of-its-binding-sites. At low substrate (tyramine) concentration (1-5 mM), a sigmoidal kinetics was preserved only at low butobendin concentration (0.155-0.31 microM). At higher butobendin concentrations (0.77 microM) a linear kinetics of DBH appeared and Km value decreased, indicating an increase in affinity of enzyme to the substrate. Interesting regulatory properties of DBH and butobendin action deserve further attention, especially for understanding a therapeutic action of butobendin in some types of heart rhythm disturbances.
Grabowska
M
M
Institute of Medical Biochemistry, Medical College of Jagiellonian University, Kraków, Poland.
Gumińska
M
M
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004299:Dopamine beta-Hydroxylase / Q000097:blood*; D004837:Epinephrine / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009638:Norepinephrine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D013237:Stereoisomerism; D014439:Tyramine / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D005029:Ethylenediamines; C030706:butobendin; D011803:Quinine; D004299:Dopamine beta-Hydroxylase; D011802:Quinidine; D009638:Norepinephrine; D014439:Tyramine; D004837:Epinephrine