Prostanoids, metabolism

Srivastava, K.C. (1990) Antiplatelet components from common food spice clove (Eugenia caryophyllata) and their effects on prostanoid metabolism. Planta Medica 56(6), 501-502. 

Codde, J.P. Beilin, L.J. Croft, K.D. Vandongen, R. Study of diet and drug interactions on prostanoid metabolism. Prostaglandins 1985, 29, 895-910. 

The (p-oxidation of leukotriene (LTB ), an important proinflammatory mediator has been documented in whole animals, isolated cells, and subcellular fractions and shown to be catalyzed by a unique P450 isoform, distinct from those involved in fatty acid and prostanoid metabolism Soon after, the cDNA coding for CYP4F3 was cloned and expressed, and recombinant CYP4F3 shown to catalyze the cp-oxidation of LTB with a of 0.71 p,M A role for... 

The bioactive PGs are further metabolized to decomposition products that are subsequently eliminated from the body by excretion in urine. This metabo-lization increases the structural multiplicity of the prostanoids. It should be emphasized that some of the metabolization products may still be bioactive. The decomposition pathways for various prostanoids are different but there are common principles for prostanoid metabolization (i) oxidation of the OH-group at C-15, forming the corresponding keto derivatives (ii) p-oxidation of the carboxyl terminus, forming the di-nor prostaglandins and (iii) co-oxidation of the... 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

A wide array of growth factors, proinflammatory molecules, including cytokines, prostanoids, and neuropeptides, contributes to the manifestation of inflammatory, neuro-degenerative, and metabolic consequences, including increased risk for triggering cell death pathways (Fig. 17.3). 

The EFA stored in the phospholipids of cell membranes are released by phospholipases, and then undergo oxidative transformation by the cyclooxygenase (COX) pathway to prostanoids and by the lipoxygenase pathway to hydroxy fatty acids and leukotrienes. The metabolism to prostanoids is catalyzed by two isoenzymes of COX, a constitutive (COX-1) and an inducible form (COX-2). The main products of COX metabolism of AA are prostaglandin E2 (PGE2), PGI A, and PGD2. In addition, A A is converted via 15-lipoxygenase to 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins, by... 

Serious drawbacks of the natural occurring compounds however do not allow their general use in therapy. The rapid metabolic deactivation21-25 and the too wide range of activity are the main problems which have to be overcome. The development of other clinical applications awaits further progress in prostanoid research and this meant a challenge to the synthetic chemists to develop chemical total syntheses which could effectively compete with biosynthesis and which could be easily modified in order to prepare analogs with improved selectivity and stability to metabolic deactivation. 

For planning and conducting these total syntheses the exact knowledge of the chemical properties of the prostanoids15 which had been studied with biosynthetic prepared prostanoids proved to be very helpful. Relatively soon it was discovered how prostanoids can be metabolised and which parts of the molecules are the targets of metabolic inactivation. Metabolism is mainly confined to the side chains. /3-Oxidation of the acid side chain leads to the essentially inactive bis- and tetra-nor acids and the oxidation of the 15-hydroxygroups results in the formation of inactive 15-ketones26-29. ... 

The plans for effective synthesis therefore aimed at common intermediates suitable for the synthesis of the natural prostanoids in high yield and for the synthesis of desirable analogues with variations in the molecule around those areas where metabolic variations occur. 

The synthesis of these heteroprostanoids in which the 13,14-double bond which is both relevant for activity and metabolic degradation of the natural prostanoids is altered by introduction of a tertiary nitrogen at position 13 started from the well known epoxide 1889S ... 

It is remarkable, that most heteroprostanoids are very weak or no substrates for the 15-hydroxy-PG-dehydrogenase. The first metabolic step observed by naturally occurring prostanoids apparently is stopped or slowed down already through the introduction of a hetero atom. 

Investigating metabolism or stability of prostanoids, radiolabeled precursors or analytes are often used. The tritiated or -labeled compounds can easily be detected without any further derivatization using online or off-line liquid scintillation, which is not impaired by any interferences derived from matrix components. Efficient but less sensitive PG analysis is possible by UV detection (190-210 nm) of underivatized substances demanding the remove of interfering contaminants or simple sample matrices like buffers or some cell supernatants. 

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