Previously we have elucidated that prostaglandins (PG) D2 is an important mast cell derived mediator in disorders of mast cell activation. Recently we discovered that PGD2 is converted to the biologically active metabolite, 9 alpha, 11 beta-PGF2 in humans via action of a 11-ketoreductase. More recently we discovered that a minimum of 16 isomeric forms of PGF2 metabolites of PGD2 are present in human plasma and urine. PGD2 appears to be an unstable compound in vivo which undergoes extensive isomerization following which reduction by 11-ketoreductase yields multiple PGF2 isomers. Studies are proposed to elucidate the mechanisms involved in the isomerization of PGD2, to identify the structures of these compounds, and to evaluate their biological activity. Mass spectrometric assays for 2 urinary metabolites will also be developed as a means to assess endogenous production of PGD2. Studies are also proposed to investigate the possibility that quantitative differences in 11-ketoreductase metabolism of PGD2 between individuals may be linked to different cardiovascular responses of PGD2 release observed in humans. We have found that 11-ketoreductase activity is present in the cellular fraction of human blood and studies are proposed to identify in which cell type(s) this activity is present. Finally, we have demonstrated that PGD2 dehydration products are formed in vivo and that in vitro these compounds readily form conjugates with glutathione. Others have demonstrated that PGD2 dehydration products exert anti-tumor activity. Studies are proposed to examine whether the active moiety responsible for this effect may be a glutathione or related conjugate. Other possible biological actions of these conjugates will be evaluated and assays for these compounds will be developed to assess their formation in vivo in humans.
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