(5Z,13E)-(15S)-9 alpha,11 beta,15-trihydroxyprosta-5,13-dien-1-oic acid (9 alpha,11 beta-prostaglandin F2): formation and metabolism by human lung and contractile effects on human bronchial smooth muscle.
Prostaglandin D2 (PGD2) was recently found to be stereospecifically converted to the compound (5Z,13E)-(15S)-9 alpha,11 beta,15-trihydroxyprosta-5,13-dien-1-oic acid (9 alpha,11 beta-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 9 alpha,11 beta-PGF2 and the contractile effects of 9 alpha,11 beta-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 9 alpha,11 beta-PGF2 at a rate of 3.46 +/- 0.94 pmol per min per mg of protein. 9 alpha,11 beta-PGF2 was found to contract human bronchial rings in a dose-dependent fashion with a potency virtually identical with that of both PGD2 and PGF2 alpha, 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 9 alpha,11 beta-PGF2. 9 alpha,11 beta-PGF2 was also found to be a very poor substrate for the lung 15-hydroxyprostaglandin dehydrogenases. Thus, once formed, 9 alpha,11 beta-PGF2 would not be expected to be rapidly inactivated in situ by these metabolic enzymes. These results suggest that 9 alpha,11 beta-PGF2 may participate along with other putative mediators in the pulmonary allergic response in humans.
Seibert
K
K
Sheller
J R
JR
Roberts
L J
LJ
D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D015237:Dinoprost; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011453:Prostaglandins / Q000378:metabolism; D011460:Prostaglandins F / Q000378:metabolism*
D011453:Prostaglandins; D011460:Prostaglandins F; D015237:Dinoprost; D006911:Hydroxyprostaglandin Dehydrogenases; C031051:prostaglandin-F synthase