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

In 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 .times. g supernatant of human liver exclusively to a single more polar compound that had a mass spectrum essentially the same as that of prostaglandin F2.alpha. (PGF2.alpha.). However, this compound could be chromatographically separated from PGF2.alpha. and failed to form a butylboronate derivative. The structure of this compound was established as 9.alpha.,11.beta.-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (9.alpha.,11.beta.-PGF2) by comparison of its chromatographic and mass spectra characteristics with authentic 9.alpha.,11.beta.-PGF2. This compound was found to be biologically active by demonstrating increases in blood pressure in rats in a dose-related fashion following intravenus administration. By using a mass spectrometic 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 9.alpha.,11.beta.-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. 9.alpha.,11.beta.-PGF2 is structurally a unique prostaglandin, is enzymatically formed, is produced in vivo in humans, and is biologically active.