Fluphenazine phototoxicity: a mechanism involving the trifluoromethyl group

Fluphenazine is a neuroleptic drug used for the long-term treatment of mental disorders, in particular in the therapy of various psychoses, including schizophrenia and mania. Occurrence of skin phototoxic and photoallergic reactions is observed when patients expose themselves to sunlight during treatment. In order to identify the mechanism of fluphenazine phototoxicity, the drug was irradiated with UVA in different solvents and in presence of nucleophilic substrates of biological relevance, like serine, lysine and a serine-containing oligopeptide. The photoproducts were characterized by mass spectroscopy and, for three of them, by NMR spectroscopy. A minor product in which N-oxidation occurred was found in all conditions. The major product which formed in water was a carboxylic acid derived from the hydrolytic defluorination of the CF3 group. In methanol and ethanol the main product was the ester of the carboxylic acid. Serine also bound fluphenazine through the same mechanism. Although with low yield, a similar product was identified in a 14-peptide irardiated in presence of the drug. Lysine did not react in the same conditions. These results suggest that photobinding of fluphenazine to serine residues of proteins may occur in vivo, thus initiating the processes leading to photoallergy.