Multi-site inhibition of human plasma cholinesterase by cationic phenoxazine and phenothiazine dyes

Two cationic phenoxazine dyes, meldola blue (MB) and nile blue (NB), and the structurally related phenothiazine, methylene blue (MethB), were found to act as complex inhibitors of human plasma cholinesterase (butyrylcholinesterase, BChE). Studied at 25 °C, in 100 mM MOPS buffer (pH 8.0), with butyry...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2007-05, Vol.461 (2), p.294-298
Main Authors: Küçükkilinç, Tuba, Ozer, Inci
Format: Article
Language:English
Subjects:
Acetylcholinesterase
Binding Sites
Binding, Competitive
Butyrylcholinesterase
Cations - pharmacology
Cholinesterase Inhibitors - metabolism
Cholinesterase Inhibitors - pharmacology
Cholinesterases - blood
Coloring Agents - metabolism
Coloring Agents - pharmacology
Humans
Meldola blue
Methylene blue
Multi-site inhibition
Nile blue
Oxazines - metabolism
Oxazines - pharmacology
Phenothiazines - metabolism
Phenothiazines - pharmacology
Plasma cholinesterase
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Summary:Two cationic phenoxazine dyes, meldola blue (MB) and nile blue (NB), and the structurally related phenothiazine, methylene blue (MethB), were found to act as complex inhibitors of human plasma cholinesterase (butyrylcholinesterase, BChE). Studied at 25 °C, in 100 mM MOPS buffer (pH 8.0), with butyrylthiocholine as substrate, the kinetic pattern of inhibition indicated cooperative I binding at 2 sites. Intrinsic K′ values ( ≡ [ I ] 0.5 2 extrapolated to [S] = 0) for MB, NB and MethB were 0.64 ± 0.05, 0.085 ± 0.026 and 0.42 ± 0.04 μM, respectively. Under the same experimental conditions the dyes acted as single-occupancy, hyperbolic-mixed inhibitors of electric eel acetylcholinesterase (AChE), with K i = 0.035 ± 0.010, 0.026 ± 0.0034 and 0.017 ± 0.0063 μM (for MB, NB, MethB); α (coefficient of competitive interaction) = 1.8–2.4 and β (coefficient of noncompetitive interaction) = 0.15–0.28. The complexity of the BChE inhibitory effect of phenoxazine/phenothiazine dyes contrasted with that of conventional ChE inhibitors which cause single-occupancy ( n = 1), competitive or mixed inhibition in both AChE and BChE and signaled novel modes of ligand interaction at (or remote from) the active site gorge of the latter enzyme.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2007.02.029