The role of lipid mediators of cell function and physiology has become increasingly evident in the last few years. Arachidonic acid is metabolized by mammalian cells through the """"""""arachidonate cascade"""""""" to a variety of products with important physiological activities and which have been implicated in the pathophysiology of many diseases. Renal microsomal cytochrome P-450 is an active catalyst for the oxygenated metabolism of arachidonic acid. Additionally, products of the epoxygenase reaction have been documented as endogenous constituents of rabbit kidneys and human urine. Studies from several groups suggest a role for renal cytochrome P-450 in the bioactivation of arachidonic acid. The available evidence suggest multiple points in which these two important constituents of mammalian cells interact with each other. The potential biological implications of these reactions are multiple and, a detailed knowledge of their associated enzymologies and biochemistry is an essential step for the elucidation of reactions and metabolites meaningful to renal function. We believe that the kidney lends itself uniquely to this purpose. The renal anatomic-physiological correlations are well established, the organ possesses the second highest body concentrations of the hemoprotein and it concentration gradients along the nephron are known. This project intends to establish the needed biochemical link between the functional studies and the synthetic efforts by providing a solid biochemical characterization of the renal cytochrome P-450 arachidonic acid oxygenase. Utilizing standard techniques of enzymology, chromatography and GC/MS analysis we plan to characterize this activity at the enzyme, cell, and organ level. We intent to provide a solid biochemical background, critical for the meaningful design and interpretation of functional studies and the synthesis of the relevant molecules.
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