Prostaglandin D2 (PGD2) was recently found to be stereospecifically converted to the compound (5Z,13E)-(15S)-9α,11β-trihydroxyprosta-5,13-dien-1-oic acid (9α,11β-PGF2) by a human liver cytosolic NADPH-dependent 11-ketoreductase enzyme. Because PGD2 is a potent bronchoconstrictor and is released into bronchoalveolar lavage fluid after allergen stimulation in patients with allergic asthma, the ability of human lung to metabolize PGD2 to 9α-11β-PGF2 and the contractile effects of 9α-11β-PGF2 on human bronchial smooth muscle were investigated. The 100,000 x g supernatant of human lung converted PGD2 in the presence of an NADPH-generating system stereospecifically to 9α,11β-PGF2 at a rate of 3.46 ± 0.94 pmol per min per mg of protein. 9α,11β-PGF2 was found to contract human bronchial rings in a dose-dependent fashion with a potency virtually identical with that of both PGD2 and PGF(2α), known potent bronchial constrictors. PGD2 was found to be a very poor substrate for human lung 15-hydroxyprostaglandin dehydrogenases and to be preferentially metabolized by lung to 9α-11β-PGF2. 9α,11β-PGF2 was also found to be a very poor substrate for the lung 15-hydroxyprostaglandin dehydrogenases. Thus, once formed, 9α-11β-PGF2 would not be expected to be rapidly inactivated in situ by these metabolic enzymes. These results suggest that 9α,11β-PGF2 may participate along with other putative mediators in the pulmonary allergic response in humans.
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 1987|