9-hydroxy-11-15-dioxo-2-3-18-19-tetranorprost-5-ene-1-20-dioic-acid and Mastocytosis

Topics: Cell Division; Histamine; Humans; Mast Cells; Mastocytosis; Prostaglandins D

Symptoms of mastocytosis have been attributed to the overproduction of both histamine and prostaglandin (PG) D2. Recently, we developed an assay for the major urinary metabolite of PGD2 (PGD-M), 9 alpha,11 beta-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid, and demonstrated that urinary excretion of this compound is markedly increased in patients with mastocytosis. It had been shown previously that measurement of the urinary excretion of histamine metabolites provides a more sensitive biochemical diagnostic indicator of systemic mastocytosis than does measurement of unmetabolized histamine. Therefore, we examined the correlation between the urinary excretion of the histamine metabolite, NT-methylhistamine, and PGD-M in urine samples from patients with mastocytosis. Urinary excretion of NT-methylhistamine and PGD-M was measured in 46 urine samples from 17 patients with histologically documented mastocytosis. Both compounds were quantified by mass spectrometry. In all urine collections showing an increase above normal (2 SD above the mean) in the excretion of NT-methylhistamine, the fold increase above normal in the urinary excretion of PGD-M was substantially greater. Further, in some urine samples from four patients whose excretion of NT-methylhistamine was consistently normal, the excretion of PGD-M was increased above normal by as much as 300%. These data indicate that quantification of the urinary excretion of PGD-M is a more sensitive biochemical diagnostic indicator of mastocytosis than is the quantification of NT-methylhistamine.

Topics: Adult; Creatinine; Female; Histamine; Humans; Male; Mastocytosis; Middle Aged; Prostaglandins D; Reference Values

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.

Topics: Anaphylaxis; Dinoprost; Drug Stability; Drug Storage; Female; Humans; Kinetics; Male; Mastocytosis; Niacin; Prostaglandin D2; Prostaglandins D; Time Factors; Urticaria Pigmentosa

The symptoms and hemodynamic alterations that accompany systemic mast cell activation have been attributed in large part to an excessive release of prostaglandin D2 (PGD2). Further, PGD2 has been implicated in the adverse effects of some pharmacologic agents (e.g. nicotinic acid). Quantitation of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical diagnosis of the disease systemic mastocytosis. However, the stable-isotope mass spectrometric assay originally developed for quantification of this metabolite has been too cumbersome for routine use. We now report improvements in the assay that greatly increase its utility by shortening sample processing and eliminating the need for purification using thin-layer chromatography. The precision and accuracy of the modified assay was evaluated and found to be comparable with the previously described assay. These modifications potentially allow wider use of the assay to explore the role of PGD2 in human disease and in the routine biochemical diagnosis of systemic mastocytosis and other disorders of mast cell activation.

Topics: Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Mastocytosis; Prostaglandins D; Reproducibility of Results

1. A sensitive and specific negative ion chemical ionization mass spectrometric assay for the major urinary metabolite of PGD2 has been developed employing a chemically synthesized [18(0)4]-labelled internal standard. 2. The finding that increased urinary excretion of this metabolite occurs in a number of clinical situations suggests that the assay may prove to be a valuable tool to explore the role of PGD2 in the pathophysiology of human disease.

Topics: Asthma; Bronchoalveolar Lavage Fluid; Histamine; Humans; Hydroxyprostaglandin Dehydrogenases; Hypercholesterolemia; Indicator Dilution Techniques; Mass Spectrometry; Mastocytosis; Niacin; Prostaglandin D2; Prostaglandins D