title: Singlet oxygen mediated DNA damage induced phototoxicity by ketoprofen resulting in mitochondrial depolarization and lysosomal destabilization.
abstract: Ketoprofen (KP) is a widely used nonsteroidal anti-inflammatory drug for the treatment of osteoarthritis and various rheumatic diseases. Currently, KP is applied topically on skin as gel to treat symptoms of pain and inflammation. We have studied the photomodification of KP under natural environmental conditions. KP generates reactive oxygen species (ROS) like ¹O₂ through Type-II photodynamic reaction. ¹O₂ mediated 2'-dGuO photodegradation, single and double strand breakage were significantly induced by photosensitized KP under sunlight/UV-R exposure. Significant intracellular ROS generation was measured through DCF-DA fluorescence. Linoleic acid photoperoxidation and role of ¹O₂ were substantiated by using specific quencher like sodium azide. KP induced cell cycle arrest in G2/M phase and cell death through MTT assay. We found apoptosis as the pattern of cell death which was confirmed through caspase-3 activation, cytochrome-c release from mitochondria, up-regulation of Bax protein and phosphatidylserine translocation. Our RT-PCR result strongly supports our view point of apoptotic cell death through up-regulation of p21 and pro-apoptotic Bax genes expression. Mitochondrial depolarization and lysosomal destabilization were also parallel to apoptotic process. Therefore, much attention should be paid to the topical application of KP and sunlight exposure in the light of skin related photosensitivity and cancers.
authors.affiliation: Photobiology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow 226001, Uttar Pradesh, India. Electronic address: ratanray.2011@rediffmail.com.
authors.forename: Ratan Singh
authors.initials: RS
authors.lastname: Ray
authors.forename: Syed Faiz
authors.initials: SF
authors.lastname: Mujtaba
authors.forename: Ashish
authors.initials: A
authors.lastname: Dwivedi
authors.forename: Neera
authors.initials: N
authors.lastname: Yadav
authors.forename: Ankit
authors.initials: A
authors.lastname: Verma
authors.forename: Hari Narayan
authors.initials: HN
authors.lastname: Kushwaha
authors.forename: Saroj Kumar
authors.initials: SK
authors.lastname: Amar
authors.forename: Shruti
authors.initials: S
authors.lastname: Goel
authors.forename: Deepti
authors.initials: D
authors.lastname: Chopra
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D017484:Dermatitis, Phototoxic / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000528:radiation effects; D007660:Ketoprofen / Q000633:toxicity*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D026082:Singlet Oxygen / Q000378:metabolism* / Q000528:radiation effects; D013472:Sunlight / Q000009:adverse effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D026082:Singlet Oxygen; D007660:Ketoprofen
keywords: (1)O(2) generation; Apoptosis; DNA damage; Ketoprofen; Phototoxicity