The products of metabolism of unsaturated fatty acids by oxygenases are well established as important signaling molecules and mediators (prostaglandins, leukotrienes, and HETEs, Hydroxyeicosatetraenoic acids). Based on these precedents, the occurrence of a peculiar hydroxy fatty acid metabolite 12R-HETE in human epidermis, and particularly its prominence in proliferative skin diseases, is strongly suggestive of its significance to the pathophysiology of skin. In humans, skin is the only tissue known to produce significant amounts of 12R-HETE. There are two outstanding unresolved issues regarding 12R-HETE and its role in skin diseases (i) precisely by what enzyme or enzymatic pathway is 12R-HETE formed? and (ii) what is the biological action or activity of this putative mediator? This proposal aims to answer the first issue, the basis of 12R-HETE synthesis in skin. This will be studied by: (1) Characterization of the potential involvement of a novel lipoxygenase we have discovered in human skin, and (2) Development of a mechanistic approach that can distinguish the synthesis of 12R-HETE by monooxygenase (e.g. P450) and lipoxygenase enzymes. Characterization of the enzyme involved in 12R-HETE synthesis should allow a more focussed approach to addressing the question of the pathogenesis - knowing the enzyme involved will allow a rational appraisal of the effects of inhibitors, provide tools for the measurement of gene and protein expression, and permit quantitative assessments of changes with therapy in normal and diseased skin tissues.
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