Transformation of prostaglandin D2 to 9 alpha, 11 beta-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (9 alpha, 11 beta-prostaglandin F2): a unique biologically active prostaglandin produced enzymatically in vivo in humans.

Abstract

Transformation of prostaglandin D2 to 9cv,11,8-(15S)-trihydroxyprosta-(5Z,13E)-dien-l-oic acid (9a,11j3-prostaglandin F2): A unique biologically active prostaglandin produced enzymatically in vivo in humans (11-ketoreductase/11-epiprostaglandin Communicated by Charles R. Park, April 17, 1985 ABSTRACTIn vitro studies examining the metabolic transformation of prostaglandin D2 (PGD2) by human liver were conducted. PGD2 was found to be converted by a NADPH-dependent enzyme in the 100,000 x g supernatant of human liver exclusively to a single more polar compound that had a mass spectrum essentially the same as that of prostaglandin F2a (PGF2,). However, this compound could be chromatographically separated from PGF2. and failed to form a butylboronate derivative. The structure of this compound was established as 9a,llfi-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (9a,11P-PGF2) by comparison of its chromatographic and mass spectral characteristics with authentic 9a,11P-PGF2. This compound was found to be biologically active by demonstrating increases in blood pressure in rats in a dose-related fashion following intravenous administration. By using a mass spectrometric assay, levels of this compound in plasma and urine from a normal volunteer were 6 pg/ml and 982 ng/24 hr, respectively. In a patient with systemic mastocytosis associated with overproduction of PGD2, urinary excretion of 9a,11f-PGF2 was 6634 ng/24 hr and a circulating plasma level as high as 490 ng/ml was found during a severe episode of systemic mast cell activation. 9a,11-PGF2 is structurally a unique prostaglandin, is enzymatically formed, is produced in vivo in humans, and is biologically active.Recently we investigated the metabolism of prostaglandin D2 (PGD2) in a normal male volunteer and found that PGD2 is converted predominantly to PGF-ring compounds (1). These data provided presumptive evidence for 11-ketoreductase activity in vivo in humans analogous to evidence for this pathway of metabolism of PGD2 described in the monkey (2). Furthermore, almost all of the PGF-ring urinary metabolites of PGD2 isolated failed to form a butylboronate derivative when treated with n-butylboronic acid, suggesting that the C-9 and C-li hydroxyl groups of these metabolites were not coplanar (3). Intact PGF2 was also excreted into the urine as a metabolite of PGD2 and did not react with n-butylboronic acid. We have now undertaken in vitro studies of the conversion of PGD2 to PGF2 and report the finding that PGD2 is converted stereospecifically to 9a,11,8-(15S)-trihydroxyprosta-(5Z,13E)-dien-l-oic acid (9a,11, by an enzyme in the 100,000 X g supernatant of human liver, that this compound is present in plasma and urine from humans, and that this compound is biologically active. EXPERIMENTAL PROCEDURESMaterials and Methods. Unlabeled PGD2, PGF2,, and 9a,11i-PGF2 were the generous gifts of John Pike and Gordon Bundy of Upjohn. Synthesis of 9a,11f3-PGF2 was accomplished with modifications of procedures described previously (4). The synthetic 9a,li,-PGF2 contains...

9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways.

“…by human liver in vitro, Roberts and co-workers have provided convincing evidence that PGD2 is converted exclusively to 9a,1 1f-PGF2 (10). They have also shown that after infusion of radiolabeled PGD2 in a normal volunteer, at least 13 ofthe PGF ring compounds isolated in the urine had 9a, 1 (10).…”

“…shown that the predominant route of metabolism is via initial formation of the 1 l3-hydroxyl epimer of PGF2a, 9a, 1 If3-PGF2 (10)(11)(12). On examining the metabolic transformation of PGD2…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…The PGF 2α has been shown to induce uterine constriction, contraction of coronary arteries and raise blood pressure (Makino et al, 2007;Camu et al, 1992). The 9α,11β isomer of PGF 2 produces similar biological effects but it inhibits ADP-induced platelet aggregation whereas PGF 2α is devoid of such activity (Liston and Roberts, 1985). AKR1C3 (PGF synthase) has an active site which is capable of reducing both the endoperoxide group of PGH 2 and the aldehyde group of PGD 2 .…”

Evidence for mast cell activation during exercise-induced bronchoconstriction

“…The urinary excretion (mean±SE) of 9α,11β-PGF 2 Eur Respir J 1998;12: 345-350. and N τ -methylhistamine, was measured before and after exercise challenge in a group of asthmatics with a history of EIB. The major cyclooxygenase product of mast cells PGD 2 , is metabolized in the lung, via the action of the reduced nicotinamide adeine dinucleotide phosphate (NADPH)-dependent enzyme 11-ketoreductase to 9α, 11β-PGF 2 , and is excreted intact into the urine [24]. Since PGD 2 production in humans is restricted almost exclusively to the mast cell [25], PGD 2 and its metabolites may be employed as mast cell markers.…”