High-throughput screening strategy for photogenotoxic potential of pharmaceutical substances using fluorescent intercalating dye.
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| Abstract |
The aim of the present study was to provide an intercalator-based photogenotoxicity (IBP) assay as a high-throughput in vitro screening system for predicting the photogenotoxic potential of pharmaceutical substances. The conditions of the high-throughput IBP assay using thiazole orange (TO), a fluorescent intercalating dye, were optimized and validated by a fluorescence titration experiment and reproducibility/robustness test. The IBP assay was applied to 27 phototoxic and 5 weak/non-phototoxic commercially available compounds, and other phototoxicity screenings were also carried out for comparison; these included the reactive oxygen species (ROS) assay for overall phototoxic potential and the DNA-photocleavage assay for photogenotoxic risk. According to the results from the comparative experiments, a decreased level of intercalated TO in the IBP assay could theoretically be related to the DNA-photocleaving behaviors of phototoxic drugs, but not to their ROS-generating abilities. The IBP assay could predict the photodynamic DNA impairment caused by irradiated drugs with a prediction accuracy of 78%. These findings suggest that the IBP assay could be a fast and reliable tool for predicting the photogenotoxic potential of a large number of drug candidates at early stages of drug discovery.
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| Authors | Yoshiki Seto, Masanori Ochi, Satomi Onoue, Shizuo Yamada |
| Journal | Journal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 52 Issue 5 Pg. 781-6 (Sep 05 2010) ISSN: 1873-264X [Electronic] England |
| PMID | 20236783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | 2010 Elsevier B.V. All rights reserved. |
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