Nabumetone induced photogenotoxicity mechanism mediated by ROS generation under environmental UV radiation in human keratinocytes (HaCaT) cell line

Abstract

Nabumetone (NB) is a non-steroidal anti-inflammatory drug (NSAID), prescribed for managing pain associated with acute/chronic rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders. Though some incidences of photosensitivity have been reported, there is limited information available on its phototoxicity potential. In this study, NB photodegraded in a time-dependant manner (0-4 h) under UVA (1.5 mW/cm 2 ), UVB (0.6 mW/cm 2 ) and natural sunlight as observed through UV-vis spectrophotometer and the results were further confirmed with Ultra High-Performance Liquid Chromatography (UHPLC). Photosensitized NB generated reactive oxygen species (ROS) as observed by lipid peroxidation, suggesting oxidative degradation of lipids in cell membrane, thereby resulting in cell damage. MTT and NRU (neutral red uptake) assays revealed that NB induced phototoxicity in concentration-dependent manner (0.5, 1, 5, 10 μg/ml) under UVA, UVB and sunlight exposure (30 min) in human keratinocytes cell line (HaCaT), with significant phototoxicity at the concentration of 5 μg/ml. Photosensitized NB generated intracellular ROS, disrupted mitochondrial and lysosomal membrane integrity, resulting in cell death. UV-induced genotoxicity by NB was confirmed through micronuclei generation, γ-H2AX induction and cyclobutane pyrimidine dimer formation. This is the first study which showed the phototoxicity and photogenotoxicity potential of NB in HaCaT cell line. We also observed that photosensit…