Isomeric prostaglandin F2 compounds arising from prostaglandin D2: a family of icosanoids produced in vivo in humans.

Abstract

Prostaglandin (PG) D2 has been shown to be transformed by human 11-ketoreductase to 9a,11f-PGF2, a biologically active metabolite that is produced in vivo. During the course of developing a mass spectrometric assay for 9a,113-PGF2, several compounds with characteristics similar to PGF2 were detected in both plasma and urine of normal humans by selected ion monitoring. Analysis of pooled plasma obtained from patients with mastocytosis during severe episodes of systemic mast cell activation associated with the release of markedly increased quantities of PGD2 was revealing in that all of these compounds were present in approximately 800-fold greater abundance compared to levels found in normal plasma, suggesting that these compounds arose from PGD2 metabolism.Complete electron impact mass spectra were obtained of these compounds in both plasma and urine; these spectra established that they were all isometric forms of PGF2. Approximately 16 isomeric PGF2 compounds were identified. Treatment with butylboronic acid indicated that the C-9 and C-11 hydroxyls were trans in approximately one-third ofthe compounds and cis in approximately two-thirds. Preliminary experiments suggest that PGD2 is a very labile compound in vivo and undergoes extensive isomerization, after which reduction by 11-ketoreductase yields a family of more stable isomeric PGF2 compounds. Elucidating the profile of biological activity of these compounds and their mechanism of formation will contribute importantly to our understanding of the biological consequences of PGD2 release in vivo. These results also bring into question the reliability of assays for PGFu and its metabolites in human biological fluids as a specific index of endogenous PGFu biosynthesis, as these assays may also measure in part isomeric PGF2 compounds arising from PGD2 metabolism.Prostaglandin (PG) D2 is the principal cyclooxygenase product produced by mast cells (1, 2). PGD2 is released in markedly increased quantities in patients during episodes of systemic mast cell activation and is a major mediator of the humoral manifestations of such episodes (3, 4). PGD2 has also been considered as a potential mediator in the human pulmonary allergic response (5) and recently has been shown to be released into the lower respiratory tract during acute antigen challenge in patients with allergic asthma (6). PGD2 is metabolized in vivo predominantly via a 11-ketoreductase pathway to PGF-ring metabolites (7)(8)(9). In vitro studies demonstrated that human liver 11-ketoreductase stereospecifically transforms PGD2 to 9a,11/3-PGF2 (10), a finding that subsequently has been generalized to 11-ketoreductase metabolism of PGD2 in other human and animal tissues and organs (11)(12)(13)(14). Importantly, 9a,11,8-PGF2 has been shown to be produced in vivo and to be a biologically active metabolite that is a pressor substance in the rat (10), inhibits platelet aggregation (11, 15), and causes both human coronary and human bronchial smooth muscle to contract (13,14).Because of the potential importa...

Key issues in F2-isoprostane analysis

“…In 1988, Wendelborn et al [19] reported that healthy subjects exhibited 48-460 pg/ml of urinary PGF 2 -like compounds. The corresponding levels for circulating PGF 2 -like compounds was in the range 1-12 pg/ml.…”

“…Total lipid extracts from plasma and urine from the above-mentioned samples were therefore treated with n-butylboronic acid. n-Butylboronic acid forms The determination of prostaglandin metabolites in human urine [16] 1988 Discovery of PGF 2 isomers derived from PGD 2 metabolism in human plasma and urine [19] 1990…”

The Isoprostanes: Unique Prostaglandin-Like Products of Free-Radical-Initiated Lipid Peroxidation*

“…In aqueous solutions, however, PGD 2 in an unstable compound that undergoes isomerization of the lower side chain and these isomers can likewise be reduced by 11-ketoreductase to yield isomers of 9α,11β-PGF 2 [12]. In studies undertaken to further characterize these compounds utilizing a gas chromatographic (GC)/mass spectrometric (MS) assay, we found that in plasma samples from normal volunteers that were processed and analyzed immediately, a series of peaks were detected possessing characteristics of F-ring PGs (Fig.…”

The isoprostanes—25 years later

“…In aqueous solutions, however, PGD 2 is an unstable compound that undergoes isomerization of the lower side chain and these isomers can also be reduced by 11-ketoreductase to yield isomers of 9α,11β-PGF 2 α [4]. In studies undertaken to further characterize these compounds utilizing mass spectrometry, it was found that when plasma samples from normal volunteers were processed and analyzed immediately, a series of peaks were detected possessing characteristics of F-ring PGs.…”