title: Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites.
abstract: Chlorpromazine (CPZ) is an anti-psychotic drug widely used to treat disorders such as schizophrenia or manic-depression. Unfortunately, CPZ exhibits undesirable side effects such as phototoxic and photoallergic reactions in humans. In general, the influence of drug metabolism on this type of reactions has not been previously considered in photosafety testing. Thus, the present work aims to investigate the possible photo(geno)toxic potential of drug metabolites, using CPZ as an established reference compound. In this case, the metabolites selected for the study are demethylchlorpromazine (DMCPZ), didemethylchlorpromazine (DDMCPZ) and chlorpromazine sulfoxide (CPZSO). The demethylated CPZ metabolites DMCPZ and DDMCPZ maintain identical chromophore to the parent drug. In this work, it has been found that the nature of the aminoalkyl side chain modulates the hydrophobicity and the photochemical properties (for instance, the excited state lifetimes), but it does not change the photoreactivity pattern, which is characterized by reductive photodehalogenation, triggered by homolytic carbon-chlorine bond cleavage with formation of highly reactive aryl radical intermediates. Accordingly, these metabolites are phototoxic to cells, as revealed by the 3T3 NRU assay; their photo-irritation factors are even higher than that of CPZ. The same trend is observed in photogenotoxicity studies, both with isolated and with cellular DNA, where DMCPZ and DDMCPZ are more active than CPZ itself. In summary, side-chain demethylation of CPZ, as a consequence of Phase I biotransformation, does not result a photodetoxification. Instead, it leads to metabolites that exhibit in an even enhanced photo(geno)toxicity.
authors.affiliation: Instituto de Tecnología Química UPV-CSIC/Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Palumbo
authors.affiliation: Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Lainez
authors.affiliation: Instituto de Tecnología Química UPV-CSIC/Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Limones-Herrero
authors.affiliation: Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain.
authors.forename: M Dolores
authors.initials: MD
authors.lastname: Coloma
authors.affiliation: Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Escobar
authors.affiliation: Instituto de Tecnología Química UPV-CSIC/Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.
authors.forename: M Consuelo
authors.initials: MC
authors.lastname: Jiménez
authors.affiliation: Instituto de Tecnología Química UPV-CSIC/Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain. Electronic address: mmiranda@qim.upv.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Miranda
authors.affiliation: Instituto de Tecnología Química UPV-CSIC/Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain; Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain. Electronic address: iandreur@qim.upv.es.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Andreu
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism*; D002746:Chlorpromazine / Q000378:metabolism*; D020552:Comet Assay; D004578:Electron Spin Resonance Spectroscopy; D004587:Electrophoresis, Agar Gel; D008745:Methylation
chemical_list: D014150:Antipsychotic Agents; D002746:Chlorpromazine
keywords: Comet assay; Excited states; Laser flash photolysis; Metabolites; Photosensitized DNA damage; Phototoxicity