This project is directed to examine molecular aspects of normal and abnormal reactions of human skin to solar ultraviolet radiation (erythema, edema, drug-induced photosensitivity reactions and skin cancer). Until recently, our studies on the effects of ultraviolet radiation (UVB and psoralens + UVA or PUVA) were directed towards examining cellular and molecular changes associated with DNA. We now wish to examine the effects of reactive O2 species [singlet oxygen (1-O2), superoxide anion (O2), hydroxy radicals (OH)] on epidermal membranes, DNA, enzymes, and skin cancer. We propose basic multidisciplinary studies, in the form of six projects, to develop new knowledge regarding ultraviolet-induced erythema and skin photosensitization reactions and the susceptibility of mammalian skin to cancer. In Project I, we will examine variations of superoxide dismutase (SOD) activity and 1-O2- and O2-producing ability in skin of individuals with Skin Types I, II, III, IV, V, and VI, and in various strains of mice manifesting varying susceptability to skin cancer. In Projects II and III, we propose studies on membrane-damaging changes evoked by psoralens + UVA (PUVA). Effects of 1-O2, O2, and OH will be examined on mitochondrial, lysosomal amd microsomal membranes and on associated enzymes. Additional studies are proposed to determine the release of arachidonic acid (AA) from phospholipids and to ascertain whether selective scavengers of free radicals and quenchers of 1-O2 and O2 [sodium azide, SOD, 1,4-diaza-bicyclo-(2,2,2)-octane, beta-carotene, urate, etc.] will inhibit release of AA and activation of phospholipase A2. In Project IV, we will examine whether erythema reactions induced by UVC, UVB, UVA, and PUVA are O2 dependent and are influenced by formation of reactive O2 species. Project V involves studies on detection and repair of photodamaged DNA in mammalian skin (keratinocytes, melanocytes, lymphocytes, etc.) using specific immune serum against DNA-8-MOP photoadducts and against UVB-induced thymine-thymine adducts. Project VI-A involves transformation studies of fibroblasts and keratinocytes by photosensitizing agents, psoralens and isopsoralen, used in photochemotherapy. Project VI-B is designed to learn whether PUVA-associated risk of cancer can be minimized by using agents known to quench reactive forms of O2 (SOD, beta-carotene, alpha or delta-tocopherol, retinoic acid, etc.) These investigations should lead to new knowledge of preventing cellular damage, skin erythema, and skin cancer induced by UV radiation and PUVA.
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