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Photoaddition of fluphenazine to nucleophiles in peptides and proteins. Possible cause of immune side effects.
- Source :
-
Chemical research in toxicology [Chem Res Toxicol] 2007 Oct; Vol. 20 (10), pp. 1470-6. Date of Electronic Publication: 2007 Sep 21. - Publication Year :
- 2007
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0893-228X
- Volume :
- 20
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Chemical research in toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 17883260
- Full Text :
- https://doi.org/10.1021/tx700123u