MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY

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Photosensitization can result when light interacts with endogenous or exogenous chemical agents in the skin and eyes. This process can produce undesirable clinical consequences, such as phototoxicity (exaggerated sunburn), photoallergy, or photocarcinogenicity; or it can have beneficial effects as in tumor photodynamic therapy (PDT) and coal tar, anthralin or psoralen (PUVA) therapy for psoriasis. The objective of this research project is to elucidate the photochemical mechanisms whereby these photosensitizers exert their toxic effects. Fluoroquinolones (FQ) are a relatively new class of antibiotics that are useful in the treatment of gram-negative bacterial infections. When used in humans FQ' often cause phototoxicity. Recent studies have shown that lomefloxacin causes squamous cell carcinomas in hairless mice injected with this drug and irradiated with UV-A (315-400) nm. We have studied the photochemical properties of lomefloxacin and related FQ's to determine why these drugs as a class are phototoxic and why lomefloxacin is photocarcinogenic. Singlet oxygen (1O2) and superoxide yields for the FQ antimicrobials do not correlate with their phototoxic potentials. However, photocleavage of pBR322 DNA by the FQ antibiotics is at least 10-fold more efficient for difluorinated quinolones (lomefloxcin and fleroxacin) than for monofluorinated analogs. 1O2 does not induce photocleavage. Futhermore, the inhibitory effect of O2 on the induction of frank strand breaks makes it unlikely that superoxide could play a major role in the photocleavage of DNA by these antibiotics. Photocleavage might result from a free-radical mechanisms involving hydrogen-atom-abstraction from the sugar-phosphate backbone by an- antibiotic-derived radical. Oxazepam is a commonly prescribed anti- anxiety drug that has been shown to induce the formation of hepatocellular adenomas and carcinomas in mice. Studies conducted by the National Toxicology Program have shown that mice chronically treated with this drug develop cataracts. We have found that while the drug itself is a poor generator of singlet oxygen, one of its metabolites, 6-chloro- 4-phenyl-2(1H)-quinazoline, is able to sensitize the formation of 1O2 with high efficiency.