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(5Z,13E)-(15S)-9α ,11β ,15-trihydroxyprosta-5,13-dien-1-oic Acid (9α ,11β -prostaglandin F2): Formation and Metabolism by Human Lung and Contractile Effects on Human Bronchial Smooth Muscle
Karen Seibert, James R. Sheller and L. Jackson Roberts
Proceedings of the National Academy of Sciences of the United States of America
Vol. 84, No. 1 (Jan. 1, 1987), pp. 256-260
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/28988
Page Count: 5
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Prostaglandin D2 (PGD2) was recently found to be stereospecifically converted to the compound (5Z,13E)-(15S)-9α ,11β ,15-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 × 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 PGF2α, 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.
Proceedings of the National Academy of Sciences of the United States of America © 1987 National Academy of Sciences