1. Photoaddition of fluphenazine to nucleophiles in peptides and proteins. Possible cause of immune side effects.
- Author
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Caffieri S, Miolo G, Seraglia R, Dalzoppo D, Toma FM, and van Henegouwen GM
- Subjects
- Agranulocytosis chemically induced, Agranulocytosis immunology, Amino Acids chemistry, Amino Acids immunology, Antipsychotic Agents chemistry, Antipsychotic Agents immunology, Carboxylic Acids analysis, Cysteine chemistry, Cysteine radiation effects, Fluphenazine chemistry, Fluphenazine immunology, Hydrogen-Ion Concentration, Lysine chemistry, Lysine radiation effects, Peptides chemistry, Peptides immunology, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tyrosine chemistry, Tyrosine radiation effects, Ultraviolet Rays, Amino Acids radiation effects, Antipsychotic Agents radiation effects, Fluphenazine radiation effects, Peptides radiation effects, Photolysis radiation effects
- Abstract
By the action of UVA light, fluphenazine reacted with nucleophiles through a mechanism involving defluorination of its trifluoromethyl group, giving rise to carboxylic acid derivatives that were easily detected by electrospray mass spectrometry. This photoreaction took place with alcohols, sulphydryls, and amines. When irradiation of fluphenazine was carried out in the presence of an amino acid at pH 7.4, the alpha-amino group was covalently bound to the drug. With amino acids possessing a further nucleophilic residue on the side chain, such as lysine, tyrosine, and cysteine--but not serine--both groups reacted, resulting in a fluphenazine-amino acid-fluphenazine diadduct. The same occurred with the physiological peptide glutathione (gamma-glutamylcysteinylglycine). By means of MALDI mass spectrometry, it was shown that fluphenazine also covalently bound to peptides and proteins such as calmodulin. This binding may result in the formation of antibodies, ultimately leading to the destruction of the granulocytes and thus suggesting that photoactivation of this drug may play a role in its clinical side effects, such as agranulocytosis.
- Published
- 2007
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