The photomutagenicity of fluoroquinolones and other drugs

Induction of DNA damage as a consequence of exposure to UV light has been e stablished as the major and still increasing cause of skin cancer. Absorpti on of the photon energy may be either directly by the DNA molecules (for wa velengths <320 nn) or may be by endogenous or exogenous chemicals (sensitiz ers) with the potential of energy or electron transfer to DNA. Oxygen-media ted reactions (often called type II reactions) appear to be the most import ant mechanism since molecular oxygen is a good and abundant substrate for t riplet excited sensitizers. Energy transfer to molecular oxygen is possible for wavelengths in the near UV and in the visible part of the solar spectr um since the energy of the excited oxygen molecule (O-1(2)*) is comparative ly low. A few light-absorbing pharmaceuticals have long been known to cause photo(geno)toxic effects. Notably psoralene and chlorpromazine derivatives have been established as photomutagens and the reaction mechanisms have be en identified. The fluoroquinolone antibiotics have more recently been reco gnized as being photomutagenic. The type of DNA damage and the modulation b y antioxidants indicate the involvement of reactive oxygen species (ROS) bu t other mechanisms are also reported at least for some derivatives. In rout ine genotoxicity studies we observed a photomutagenic activity of a compoun d under development as an anxiolytic agent in the Ames tester strain TA102 at 'normal laboratory illumination' conditions. Further investigations show ed strong photogenotoxic activity in tests for gene mutations and chromosom al aberrations in mammalian cells. The compound proved to be a potent O-1(2 )-producer. The finding led to termination of development but in the course of studies several structural analogues have been tested for which structu re activity relationships will be described. The relevance of photogenotoxi c properties of drugs for predicting adverse effects in man will be discuss ed. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.