Photosensitized membrane damage is responsible for the cutaneous phototoxicity of certain drugs and can be used for therapy if the photosensitization is directed to abnormal tissue. The goals are to predict the photosensitizing potential of drugs and to develop therapies based on in vivo photochemistry. These goals require understanding of the molecular mechanisms for photosensitization.
The specific aims are: 1) To determine whether the photochemistry of three phototoxic compounds in solution and in liposomes can be used to predict the membrane photosensitizing ability of the drugs. The photochemical mechanisms for amiodarone, benoxaprofen and the phototoxic metabolite of piroxicam will be determined using kinetic and quenching studies and product analysis. Endpoints for membrane damage will include lysis and covalent crosslinking of membrane proteins using red cells, and enzyme inhibition, loss of membrane integrity, and inhibition of drug binding using human diploid fibroblasts. 2) To determine the mechanism(s) for a potential light-initiated tumor therapy based on cyanine dye photosensitization of the inner mitochondrial membrane. The probable locations for the dyes will be determined using absorption and fluorescence and radioactivity labelled dyes. The dye-photosensitized inhibition of specific steps in electron transport and phosphorylation reactions of oxidative phosphorylation will be assessed. Possible molecular photochemical mechanisms will be evaluated including covalent binding of dye to proteins, oxidation of membrane components, and involvement of toxic photoproducts of the dye. The results of these studies will be used to rationally design dyes with optimal localizing and photosensitizing abilities.
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