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, as in phototoxicity (exaggerated sunburn) and/or photoallergy; 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. Sunlight has been implicated in the high incidence of skin cancer found in patients receiving 6-mercaptopurine (6- MP) in the form of its pro-drug azathioprine. Spin trapping studies have shown that excited state 6-mercaptopurine, is a highly efficient reducing agent that in aerobic solution generates superoxide. In addition, 1,3(6-MP)* can oxidize ascorbate, formate and reduced glutathione. A decrease in the concentration of ascorbate and/or glutathione in the skin would render the tissue more susceptible to oxidative stress. Irradiation of purine-6-sulfonate, the main 6-MP photoproduct, generates the highly oxidizing SO3- anion radical, which is known to cleave DNA. Thus, 6-MP, its photoproducts and metabolites generate a variety of free radicals that may be involved in the etiology of skin cancer induced by azathioprine. 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~s occasionally cause phototoxicity (exaggerated sunburn). Since the FQ~s contain both acidic (carboxyl) and basic (amino) moieties the drugs exist in solution in a variety of ionized states depending on pH. They also chelate divalent metal ions eg Ca2+ and Mg2+ which may modify their photochemistry. We have characterized the spectroscopic and photochemical properties of the FQ norfloxacin as a function of pH and divalent metal ion concentrations. At physiological pH norfloxacin generates both singlet oxygen and superoxide which may be responsible for the drug~s phototoxicity.