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of this application and would recommend approval but not vitb a high priority

ed. Smoking is known to increase the activ=iy of some enzymes such as placental cytochrome P450 by enzyme :.nduction. The products of the lipoxygenase and cytochrome T-'450 monooxygenase reactions are similar. He can find only one study dealing with the effect of smoking on lipoxygenase activit:y. It did not distinguish the activity of lipoxygenase versus P450 monoox- genase. He plans to initiate his studies by examining the fate of 14C-arachidonate that has been incubated with placental or umbilical microsomes or 10,000 x g supernatant solutions that have been isolated from normal and preeclamptic pregnancies of smokers and non-smokers. These incubatior_s will be conducted in the absence and presence of indomethacin, NADPH and of the cytochrome P450 inhibitors, SKF-525 and others. Arachidonate metabolites whose synthesis is blocked by these inhibitors will be identified by the use of HPLC, or mass spectrometry if necessary. The final question to be asked is do products of smoking alter the arachidonic acid cascade in preeclampsia by being cofactors, substrates, or inhibitors of enzymes involved in that cascade. INVESTIGATOR: The principal investigator is a 51 year old physician associate professor in the Department of Medicine. He has served in the Departments of Pharmacology and in the Laboratory of Pharmacol- ogy of the Baltimore Cancer Research Center. He has a total of 38 publications and lists several dealing with studies of human placental prostaglandins. Three of these ha•Te been submitted for publication. BUDGET: The budget for the first year appears inflated. About 60% is for his salary and that of a senior research technician to be named. $14,000 is requested for a bioscan inage scanner. He has an NIH grant in the amount of $12,570 wh:ich is a carry over grant while his competing renewal is being considered for funding. He claims that this NIH grant comp:Lements the one we are considering. I believe the budget 9s high, but I really don't see where it can be cut. CRITIQUE, SUMMARY AND CONCLUSIONS: I am not a prostaglandin chemist, so it ie difficult for me to be critical of the proposal as written. The things stated seem to make sense, and if they could be brought to a logical conclusion, the information could be potenti,ally valuable in the handling of patients with eclampsia. The problem as I see it is that Jarabak is net a productive investigator and because of his poor publication record I am not sure that the experiments will be brought to fruition in the way they should be. Accordingly, I cannot wax strong in my support

3/24/87 CC: DRS. JLICOBS01d,SOMMERS,SCIENTIFIC STAFF Council for Tobacco Research - Pierce Grant Application No. 2118 Applicant: Joseph Jarabak, M.D., Ph.D., The University of Chicago, Illinois Title: "The Effect of Smoking on --:icosaroid Metabe- lism in Normal and the Preeclamptic Pregnan- cies" DESCRIPTION: An ir:verse correlation between the number of cigarettes smoked daily during pregnancy and the incidence of preeclampsia has been reported. Recently there has been evidevice to suggest an etiologic role in preeclampsia for prostablandins and other products of the arachidonic acid cascade. Prostacyclin is a labile vasodilator and inhibitor of platelet aggregation. Its concentration is depressed in the umbilical ard placental vasculature of preeclamptic patients. Other studies have demonstrated a decreased incidence of preec?e3mpsia following the administration of nonsteroidal inhibitors of prostaglandin and thromboxane synthesis. To date no one has Lested the hypothesis that the salutary effects of cigarette smoking on preeclampsia are due to alterations in one or more steps :Ln the prostaglandin cascade. As a consequence three specific aims are outlined. The first asks the question are the relative amounts of products from the arachidonic acid cascade affected b.~ whether an individual has preeclampsia or is a smoker. A11 of the products in the arachidonic acid cascade are catabolized by various enzymes and to date no investigators of preeclampsia, interested in PGFla or cyclooxygenase activity, have ever measured either the activity of the enzyme or the relative amounts of the various catabolic products. He proposes to ~Drovide an overal.ll picture of the fate of the arachidonic acid in normal placental tissue and umbilical vessels by administerin; 14C-arachidonate to homogenates of placental tissue and umbili.cal vessels. The products will then be separated by thin laye-r chromatography or HPLC and identified by the use of authentic standards. He will examine the effects of metal ions, reducing agents, and cofac- tors on the conversion. This should tell him the fate of arachidonic acid in placental tissues. The second experiment asks the question are the effects off preeclampsia on specific enzymes in the ara.c.idonic acid cascade nullified by smoking? He points out there are a number of enzymes in the arachidonic acid cascade whosa activities in placental tissues or umbilical vessels mav be influenced by preeclampsia or smoking. The conclusion has been reached by others with little substantiation that PGH synthase is less active in preeclamptic than in normal pregnancies. He will examine this conclusion directly. The methods are all describ-