Biomedical subjects
Publications and source records attributed to F F Sun.
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The transformation of 6-keto-PGF1 alpha to two prostacyctin metabolites, 2,3-dinor-6-keto-PGF1 alpha (I) and 2,3-dinor-6,15-diketo-13,14-dihydro-PGF1 alpha (II) by Mycobacterium rhodochrous UC-6176 is described. The finding that the bacterium oxidized 6-keto-PGF1 alpha to the 6,15-diketo metabolite II shows that it contains 15-hydroxy prostaglandin dehydrogenase and delta 13 reductase enzyme systems.
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When tritium labeled prostacyclin (PGI2) or 6-keto PGF1 alpha were injected i.v. into rats, one-third of the dose appeared in the liver after 15 min. Significant levels of radioactivity (8--16%) were also found in the small intestine. These observations plus the prominant fecal excretion of PGI2 radioactivity suggest that PGI2 and/or its metabolites undergo biliary excretion and enterohepatic recirculation. We therefore investigated PGI2 excretion and metabolite composition of the bile in bile duct cannulated rats. After a single bolus i.v. injection of 11-[3H] PGI2 into these rats, an average of 37% of the administered radioactivity was excreted in the bile within 3 hr. A number of metabolites were detected in the bile. The major metabolites were isolated and identified as 2,3-dinor-6-keto-PGF1 alpha and 13,14-dihydro-2,3-dinor-6,15-diketo-PGF1 alpha-glucuronide which each accounted for approximately one-third of the radioactivity in the bile. Other metabolites include 6-keto PGF1 alpha, 13,14-dihydro-2,3-dinor-6,15-diketo-PGF1 alpha, 13,14-dihydro-2,3-dinor-6,15-diketo-20-carboxyl PGF1 alpha and 2,3,4,5,6-pentanor-PGF1 alpha-gamma-lactone. We conclude that the liver plays a pivotal role in the inactivation and disposition of prostacyclin. The predominate metabolic pathways occurring in the liver are probably beta-oxidation and glucuronic acid conjugation.
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6-Keto-prostaglandin E1 (6-keto-PGE1) was found to have a similar potency to prostacyclin (PGI2) as an inhibitor of platelet aggregation. It caused a time and concentration dependent inhibition of ADP, collagen and epinephrine induced platelet aggregation, the dose ratios for 70% inhibition by 6-keto-PGE1, PGI2 and PGE1 being approximately 1 : 1 : 13. In doses similar to those of PGI2, 6-keto-PGE1 partially inhibited the release of [3H]-serotonin from platelet-rich plasma induced by collagen.
Incubation of [3H]arachidonic acid with the 17,000-g supernatant from homogenates of human neutrophils in the presence of indomethacin generated the unique metabolites 9-OH-5,7,11,14-eicosatetraenoic acid (9-HETE) and 8-HETE, in addition to 12-HETE, 11-HETE and 5-HETE. The human neutrophil chemotactic activity of the HETE products exhibited a rank-order of potency with 5-HETE greater than 8-HETE = 9-HETE greater than 11-HETE = 12-HETE. The expression of chemokinetic activity as well as chemotactic activity suggested that the endogenous production of these principles may influence the mobility of human neutrophils.
In the isolated rabbit kidney perfused with Tyrode's solution, we examined the metabolism of radiolabeled prostacyclin. [9-3H]Prostacyclin was infused into the kidney and the radiolabeled products from the renal venous effluent were separated by thin layer chromatography and identified by gas chromatography-mass spectrometry. The major products were 7,9-dihydroxy-4,13-diketo-dinor-prostanoic acid and dinor-6-keto-prostaglandin F1alpha. They represented 25% and 10% of the total radioactivity, respectively. Metabolism of prostacyclin by the kidney may be an important determinant of the effects of prostacyclin on renal function.
The absorption of dinoprost (prostaglandin F2 alpha) and its methyl ester in rat jejunum was studied. A 22-cm segment of rat jejunum was cannulated at both ends and connected to an oscillating perfusion pump system. The mesenteric vasculature supplying this isolated segment also was cannulated and perfused with Kreb's bicarbonate buffer with dextran. Solutions of 3H-dinoprost or its methyl ester were introduced into the lumen and oscillated through the segment. The disappearance of radioactivity from the lumen and the appearance of radioactivity in the vascular perfusate were monitored. The metabolite patterns in the vascular perfusate were analyzed by TLC. A lag between the time the drug disappeared from the lumen and the time it appeared in the mesenteric circulation was detected. This lag was longer for the methyl ester than for the free acid, even though the ester disappears from the lumen faster than does the free acid. Upon removal of dinoprost from the gut lumen, a gradual decrease in the amount of drug appearing in the mesenteric circulation could be detected. However, with the ester, a slight increase could be observed for approximately 0.5 hr, followed by a decrease. Metabolism by the gut wall appears to be greater for the ester than for the acid. The results suggest that, although the ester disappears from the lumen more quickly than does the acid, it actually penetrates to the blood at a slower rate and undergoes greater metabolism.
The in vivo metabolism of 6-keto PGF1 alpha was investigated in rats. Following continuous intravenous infusion for 14 days the urinary metabolites were isolated and identified. A substantial amount of unchanged 6-keto PGF1 alpha was recovered in the urine. The metabolic pattern very closely resembles that of PGI2 in rats. Metabolites were found which represented 15-dehydrogenation, beta-oxidation, omega and omega-1-hydroxylation and oxidation. Previous work showed that 6-keto PGF1 alpha is very poorly oxidized by 15-PGDH. We administered 15-[H3]-PGI2 and 15-[H3]-6-keto PGF1 alpha to rats and measured urinary tritiated water as an index for in vivo 15-PGDH activity. The results showed that PGI2 and 6-keto PGF1 alpha were both oxidized to the 15-keto product, although the rate of oxidation of PGI2 was greater than that of 6-keto PGF1 alpha. We concluded that the administered PGI2 was oxidized by 15-PGDH before hydrolysis to 6-keto PGF1 alpha. A portion of the dose is probably hydrolzyed before 15-dehydrogenation.
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Following a single intravenous administration of [11-3H]prostacyclin in rat, 77% of the administered dose was excreted within 3 days with 33% in urine and 44% in feces. Urinary metabolites were accumulated by chronic intravenous infusions of [11-3H]prostacyclin for 14 days. The drug was extensively metabolized and the structures of seven metabolites were elucidated by combined gas chromatography and mass spectrometry. The urinary products include the dinor and 19-hydroxy dinor derivatives of 6-keto-PGF1alpha and 13,14-dihydro-6,15-diketo-PGF1alpha, omega-hydroxy and omega-carboxyl dinor derivates of dihydro-6,15-diketo-PGF1alpha, and a dihydrodiketotetranordicarboxylic acid. The metabolic pathways of PGI2 in rat are similar to that of PGF2alpha.
The activity of 15-hydroxyprostaglandin dehydrogenase has been shown to be high in both mesenteric arteries and veins; the present study suggests that it may be responsible for the inactivation of prostacyclin (PGI2). The cytoplasmic fractions of bovine mesenteric arteries and veins were incubated with radiolabeled PGI2 in the presence of NAD+ or NADP+. The substrate was rapidly converted to a product, which was isolated and identified as 6,15-diketo prostaglandin F1alpha, (6,15-diketo-PGF1alpha) by thin layer chromatography and gas chromatography-mass spectrometry. The initial reaction rate began to level off after less than 1 min of incubation at 37 degrees C. When radiolabeled 6-keto-PGF1alpha, the stable hydrolysis product of PGI2, was used as substrate under the same conditions, 97% was recovered unmetabolized after 2 min of incubation. Catabolism of PGI2 may be a major determinant of its levels in blood vessels and, therefore, may be of crucial importance to regulating the action of PGI2. Further, estimation of PGI2 generation by either tissues or organs may be misleading if only 6-keto-PGF1alpha is measured.
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