CORNEAL ARACHIDONATE METABOLITES VIA CYTOCHROME P450

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The epithelial cell layers of the cornea can be characterized as a "tight" ion transporting functional syncytium which serves both as a protective barrier to the ocular surface, and as an adjunct fluid- secreting layer assisting the corneal endothelium in the regulation of stromal hydration and, thereby, contributing to the maintenance of corneal transparency. Transport properties of the corneal epithelium are similar to those of the epithelial cells of the thick ascending limb of Henle's loop (TALH), the nephron segment that is important for establishing the solute gradient for urinary concentration through sodium chloride coupled transport. Both transport epithelia possess active chloride transport coupled to Na+-K+-activated ATPase. Recently, we reported that cells of the TALH metabolized arachidonic acid (AA) by cytochrome P450-dependent enzyme(s) to two biologically active metabolites: one inhibits Na+-K+-ATPase and the other relaxes blood vessels. The observations that prostaglandins and other AA oxygenated metabolites may act as a mediator(s) of transport process, and the similarity of the corneal epithelium to TALH as regards ion transport mechanism, led us to investigate the possibility that the cytochrome P450-dependent AA metabolism exists in the corneal epithelium. Our preliminary results demonstrate for the first time that the epithelium of the cornea contains a cytochrome P450 species capable of metabolizing AA to several compounds. Exactly what these compounds are and whether they have biological effects on cell function and ion transport are questions which will be addressed in this study. We expect, based on parallel studies in the TALH of the kidney, that our work will reveal substances which affect Na+-K+-ATPase activity and vascular reactivity. Indeed, in a recent experiment we demonstrated the ability of one of the corneal AA metabolites to inhibit Na+-K+-ATPase of the cornea. Such an endogenous inhibitor of Na+-K+-ATPase synthesized in the cornea may have fundamental importance in ocular transport epithelia that rely on this pump mechanism. These include the corneal epithelium and endothelium, the epithelia of the ciliary body, the lens subcapsular epithelium and the retinal pigment epithelium. Furthermore, the identification of an endogenous substance which promotes vasodilatation may have significance in diverse areas of physiology and pathophysiology such as inflammatory mechanisms, control of the ocular circulation and aqueous humor dynamics.