Photochemical mutagenesis: examples and toxicological relevance.
Induction of DNA damage as a consequence of exposure to UV light has been established as the major cause of skin cancer. DNA molecules absorb photon energy directly for wavelengths <320 nm, and lead to well-characterized mutagenic DNA damage. Alternatively, endogenous or exogenous chemicals (sensitizers) may absorb light with the potential of subsequent energy or electron transfer, and lead indirectly to DNA damage. A few light-absorbing pharmaceuticals have long been known to cause photo(geno)toxic effects. Notably, psoralen and chlorpromazine derivatives have been established as photomutagens and the reaction mechanisms have been identified; the fluoroquinolone antibiotics have more recently been recognized as being photomutagenic. The type of DNA damage and the modulation by antioxidants indicate the involvement of reactive oxygen species (ROS), but other mechanisms are also reported for, at least, some derivatives. In routine genotoxicity studies, we observed the photomutagenic activity of a compound (Ro 19-8022) under development as an anxiolytic agent in the Ames tester strain TA102 under normal laboratory illumination conditions. Further investigations showed strong photogenotoxic activity in tests for gene mutations and chromosomal aberrations in mammalian cells. The finding led to the termination of drug development. Another example of a pharmaceutical for which photogenotoxic properties were observed during development is Ro 47-7737, a bisquinoline derivative of the antimalaria compound chloroquine. Also in this case, the photochemical reactivity contributed to the termination of the development process. The risk/benefit assessment for the described compounds has to take into account the human exposure situation, for example, the ability to avoid light exposure during treatment. Consideration of photochemical mutagenesis is specifically important for sunscreen ingredients. The active components of sunscreen lotions are efficient UV absorbers. Consequently, they reduce the genotoxicity of UV light and thus may be considered antimutagens. However, photodegradation to reactive molecules or energy transfer to DNA is possible, in principle, as has been reported for para-aminobenzoic acid (PABA).
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F. Hoffmann-La Roche Ltd., PRNS, Basel, Switzerland.
D000975:Antioxidants; D002471:Cell Transformation, Neoplastic; D002746:Chlorpromazine / Q000009:adverse effects; D004249:DNA Damage; D018492:Dopamine Antagonists / Q000009:adverse effects; D004781:Environmental Exposure; D024841:Fluoroquinolones / Q000009:adverse effects; D006801:Humans; D016296:Mutagenesis; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000494:pharmacology; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology*; D013473:Sunscreening Agents / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000975:Antioxidants; D018492:Dopamine Antagonists; D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D013473:Sunscreening Agents; D002746:Chlorpromazine