Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.
OBJECTIVE
Monoamine oxidase inhibitors (MAOI) are known to cause serotonin toxicity (ST) when administered with selective serotonin reuptake inhibitors (SSRI). Methylene blue (methylthionium chloride, MB), a redox dye in clinical use, has been reported to precipitate ST in patients using SSRI. MB was assessed for MAO inhibition and so for its potential to precipitate ST.


METHODS
Inhibition of purified human MAO was quantified using kinetic assays and visible spectral changes to study the interactions of MB with MAO A.


RESULTS
MB was a potent (tight binding) inhibitor for MAO A. It also inhibited MAO B but at much higher concentration. Interactions of MB with the active site of MAO A were confirmed by its action both as an oxidising substrate and as a one-electron reductant.


CONCLUSIONS
MB is a potent reversible inhibitor of MAO A with implications for gut uptake of amines when administered orally. At concentrations reported in the literature after intravenous administration, MAO B would be partially inhibited but MAO A would be completely inhibited. This inhibition of MAO A would be expected to lead to perturbations of 5-hydroxytryptamine metabolism and hence account for ST occurring when administered to patients on SSRI treatment.
Ramsay
R R
RR
Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, Scotland, UK. rrr@st-and.ac.uk
Dunford
C
C
Gillman
P K
PK
D004396:Coloring Agents / Q000378:metabolism / Q000633:toxicity*; D003627:Data Interpretation, Statistical; D003913:Dextroamphetamine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008751:Methylene Blue / Q000378:metabolism / Q000633:toxicity*; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D012701:Serotonin / Q000633:toxicity*; D013056:Spectrophotometry, Ultraviolet
D004396:Coloring Agents; D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D012701:Serotonin; D008995:Monoamine Oxidase; D008751:Methylene Blue; D004229:Dithiothreitol; D003913:Dextroamphetamine