METABOLISM OF 8 EPI PGF2 IN HEALTHY VOLUNTEERS

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Over the past ten years a wide variety of pathological conditions has been linked to oxidative stress and research in this field has undergone a tremendous growth. However, the role played by oxidative stress in the pathogenesis of human diseases is still unclear mainly due to limitation of current methodology to assess oxidant stress in vivo. Morrow et al. have discovered a series of prostaglandin-like compounds that are produced by nonenzymatic free radical catalyzed peroxidation of arachidonic acid. These isoprostanes are formed in situ from arachidonic acid esterified to phospholipids and, once released in free form, are capable of biological activity. The isoprostanes appear to be reliable markers of oxidant injury in vivo. However, auto-oxidation of arachidonic acid may lead to artifactual increase of isoprostanes in plasma and, to a more limited degree, in urine. The measurement of urinary enzymatic metabolites of the isoprostanes would overcome this problem and would provide a reliable, non-invasive and integrated index of oxidant stress in vivo. The major urinary metabolite of the isoprostane 8-epi-PGF(2a) has been recently identified as the 2,3-dinor-5,6-dihydro-8-epi PGF(2a). We have now developed gas chromatography/negative ion chemical ionization-mass spectrometry (GC/NICI-MS) techniques that enable us to quantiate specifically the urinary excretion of both 8-epi PGF(2a). We now propose to assess the urinary excretion of these compounds following infusion of increasing doses of 8-epi PGF(2a) in five healthy volunteers. In addition, we have an electrospray mass spectrometry and the technical expertise to attempt the identification of polar metabolites of infused 8-epi-PGF(2a).