The NAD+-dependent prostaglandin dehydrogenase (PGDH) catalyzes the oxidation of the 15-hydroxyl group of prostaglandins of the E and F series. This reaction represents the major route of inactivation for these reactive compounds. 15-Hydroxy compounds that did not posses the cyclopentane ring of prostaglandins also were metabolized by this enzyme. 15- Hydroxy-eicosatetraenoic acid (15-HETE) was observed to be a substrate of the lung PGDH. The PGDH has been purified from the lung of pregnant rabbits and will be used to study the metabolism of 15-HETE and other 15-hydroxy-di- and triHETEs. 15-HETE may have important biological roles in modulating 5-and 12- lipoxygenase activities of white cells and mucus secretion in the lung, thus the metabolism of 15-HETE may be important in regulating its activity. The metabolism of other omega 6hydroxy- fatty acids that contain 17- and 18-carbon atoms also will be studied. Isolated lung perfusion studies will be performed to determine if the metabolism of 15-HETE may occur in the whole lung. The enzymatic activity of the lung PGDH is induced 20- to 40-fold during pregnancy of the rabbits but our studies indicate that the amount of immunoreactive protein does not increase. An inhibitory factor of the lung PGDH was isolated from the lungs of pregnant rabbits. The inhibitor migrated with the neutral lipid fraction and the evidence suggests it consists of free fatty acids. This factor will be examined further to determine its identity and to determine if the increase in PGDH activity during pregnancy is due to changes in this inhibitor. The presence of this inhibitor is important in understanding the expression and regulation of the PGDH activity. An antibody to the PGDH has been made and will be used to localize the enzyme by immunocytochemical procedures at the light and electron microscope levels in the lung and other rabbit tissues. The anti-lung PGDH also will be used to characterize and compare the immunochemical properties of PGDH enzymes from various tissues. PGDH activity is inhibited by substances in cigarette smoke and this loss of enzymatic activity may contribute to the vascular and airway changes observed in cigarette smokers. The effects of acrolein, a reactive aldehyde in cigarette smoke, will be studied on PGDH activity. The studies described in this proposal will lead to a greater characterization of this enzyme and the function of prostaglandins and other eicosanoid derivatives in pulmonary function, in pregnancy, and in pulmonary and cardiovascular diseases.
| Okita, R T; Okita, J R (1996) Prostaglandin-metabolizing enzymes during pregnancy: characterization of NAD(+)-dependent prostaglandin dehydrogenase, carbonyl reductase, and cytochrome P450-dependent prostaglandin omega-hydroxylase. Crit Rev Biochem Mol Biol 31:101-26 |
| Okita, J R; Robertson, S J; Okita, R T (1992) Changes in ovarian NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase activity in pregnant and pseudopregnant rabbits. Prostaglandins Leukot Essent Fatty Acids 46:93-8 |
| Ensor, C M; Yang, J Y; Okita, R T et al. (1990) Cloning and sequence analysis of the cDNA for human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase. J Biol Chem 265:14888-91 |
| Okita, R T; Sinning, A R; Okita, J R et al. (1990) NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase: immunochemical characterization of the lung enzyme from pregnant rabbits. Arch Biochem Biophys 279:242-8 |
