title: An insight into the mechanisms of the phototoxic response induced by cyamemazine in cultured fibroblasts and keratinocytes.
abstract: The phototoxicity of cyamemazine (CMZ, Tercian), a neuroleptic of the phenothiazine family, has recently been reported in humans. CMZ has an absorbance maximum at 267 nm (molar absorptivity, 25,800 M(-1) cm(-1)) but a weaker molar absorptivity in the ultraviolet A (UV-A) region. CMZ exhibits a fluorescence with maximum emission at 535 nm and a quantum yield of 0.11. CMZ is a powerful photosensitizing agent toward HS 68 human skin fibroblasts and NCTC 2544 keratinocytes. At a UV-A radiation dose of 10 J/cm2, innocuous to cells in the absence of CMZ, the LD50 (lethal dose corresponding to 50% killing) are 0.5 and 1 microM for the fibroblasts and the keratinocytes, respectively, after overnight incubation with the drug. Short incubation times do not significantly alter the LD50. The CMZ-induced phototoxicity is accompanied by lipid membrane peroxidation consistent with the amphiphilic character of this photosensitizer. Keratinocytes are an order of magnitude less sensitive to the photosensitized lipid peroxidation than fibroblasts. Microspectrofluorometry reveals that lysosomal membranes are major sites of CMZ incorporation into the two cell lines because a Forster-type resonance energy transfer process occurs from CMZ to LysoTracker Red DND99 (LTR), a specific fluorescent probe of lysosomal membranes. The CMZ-photosensitized destruction of LTR demonstrates that CMZ retains its photosensitizing capacity after its lysosomal uptake.
authors.affiliation: Muséum National d'Histoire Naturelle, Photobiologie, Paris, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Morlière
authors.forename: Josiane
authors.initials: J
authors.lastname: Haigle
authors.forename: Karim
authors.initials: K
authors.lastname: Aissani
authors.forename: Paulo
authors.initials: P
authors.lastname: Filipe
authors.forename: João Nuno
authors.initials: JN
authors.lastname: Silva
authors.forename: René
authors.initials: R
authors.lastname: Santus
mesh_terms: D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D010640:Phenothiazines / Q000032:analysis / Q000633:toxicity*; D017319:Photosensitizing Agents / Q000633:toxicity*; D013050:Spectrometry, Fluorescence; D014466:Ultraviolet Rays
chemical_list: D010640:Phenothiazines; D017319:Photosensitizing Agents; C028457:cyamemazine