title: A molecular insight into the phototoxic reactions observed with vemurafenib, a first-line drug against metastatic melanoma.
abstract: The electronic properties of vemurafenib (VB) provide a rational basis for understanding its strong UVA-induced phototoxicity. Thus, solvation of hydrophobic VB by hydrogen bonding solvents controls its photophysical, photochemical and photosensitizing properties. Addition of phosphate buffered saline (PBS) to methanol (MeOH) induces a bathochromic shift of the VB absorbance spectrum and a fluorescence emission (λmax = 450 nm, quantum yield (Φ) = 0.011). Phosphorescence (λmax = 461 nm) is observed at 77 K in MeOH. 308 nm laser flash spectroscopy demonstrates that the lifetimes (τ) and quantum yields of the VB triplet state ((3)T(*)(1)) in deaerated MeOH (τMeOH = 0.41 μs, λmax ∼ 380 nm), MeOH-PBS and HSA solutions markedly depend on the microenvironment. A long-lived radical (half-life >200 μs) is also formed. The state (3)T(*)(1) is quenched by O2 and electron donors (Cys and 2'-deoxyguanosine) at a rate constant >1 × 10(9) M(-1) s(-1). UVA-irradiation of VB in air-saturated MeOH or MeOH-PBS solutions produces a UVA-absorbing photoproduct (Φ ∼ 5 × 10(-4)). VB photosensitizes Trp destruction by type I (radical formation) and type II (singlet oxygen ((1)O2) formation) photodynamic reactions (Φ = 0.005). Singlet oxygen production is further demonstrated by the VB-photosensitized His oxidation (ΦMeOH = 0.006).
authors.affiliation: INSERM, U1088, 1 rue des Louvels, 80037 Amiens, France. morliere.patrice@chu-amiens.fr and CHU Amiens-Picardie, Pôle Biologie, Pharmacie et Santé des Populations, Centre de Biologie Humaine, Laboratoire de Biochimie, D408, 80054 Amiens, France.
authors.forename: P
authors.initials: P
authors.lastname: Morlière
authors.affiliation: Instituto de Tecnología Química UPV-CSIC, Universidade Politécnica de Valencia, Avenida de Los Naranjos, s/n, 46022 Valencia, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Boscá
authors.affiliation: Department of Chemistry and QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
authors.forename: A M S
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Hospital de Santa Maria, Faculdade de Medicina de Lisboa, Clínica Dermatologica Universitaria and Unidade de Investigação em Dermatologia, Instituto de Medicina Molecular, Avenida Prof. Egas Moniz, 1699 Lisboa Codex, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: CHU Amiens-Picardie, Pôle Biologie, Pharmacie et Santé des Populations, Centre de Biologie Humaine, Laboratoire de Biochimie, D408, 80054 Amiens, France and Université de Picardie Jules Verne, UFR de Pharmacie, EA4666, 1 rue des Louvels, 80036 Amiens, France.
authors.forename: A
authors.initials: A
authors.lastname: Galmiche
authors.affiliation: INSERM, U1088, 1 rue des Louvels, 80037 Amiens, France. morliere.patrice@chu-amiens.fr and CHU Amiens-Picardie, Pôle Biologie, Pharmacie et Santé des Populations, Centre de Biologie Humaine, Laboratoire de Biochimie, D408, 80054 Amiens, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Mazière
authors.affiliation: CHU Amiens-Picardie, Pôle Biologie, Pharmacie et Santé des Populations, Centre de Biologie Humaine, Laboratoire de Biochimie, D408, 80054 Amiens, France.
authors.forename: V
authors.initials: V
authors.lastname: Nourry
authors.affiliation: Hospital de Santa Maria, Faculdade de Medicina de Lisboa, Clínica Dermatologica Universitaria and Unidade de Investigação em Dermatologia, Instituto de Medicina Molecular, Avenida Prof. Egas Moniz, 1699 Lisboa Codex, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Muséum National d'Histoire Naturelle, Département RDDM, 43 rue Cuvier, 75231 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Santus
authors.affiliation: Hospital de Santa Maria, Faculdade de Medicina de Lisboa, Clínica Dermatologica Universitaria and Unidade de Investigação em Dermatologia, Instituto de Medicina Molecular, Avenida Prof. Egas Moniz, 1699 Lisboa Codex, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Filipe
mesh_terms: D005470:Fluorometry; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008163:Luminescent Measurements; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D010782:Photolysis; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014466:Ultraviolet Rays; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D017319:Photosensitizing Agents; D013449:Sulfonamides; D000077484:Vemurafenib