A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism.
Increasing attention has focused on the role of free radicals derived from oxygen in the pathophysiology of a wide variety of disorders. One of the well-recognized targets of free radical-induced injury is peroxidation of lipids. Using a variety of approaches, we have found that a series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase mechanism involving free radical-catalyzed peroxidation of arachidonic acid. Levels of these compounds in normal human plasma and urine range from 5 to 40 pg/ml and 500 to 4000 pg/mg of creatinine, respectively. In rats, their formation was found to increase as much as 200-fold in association with marked free radical-catalyzed lipid peroxidation induced by administration of CCl4 and diquat. To explore whether these prostanoids can exert biological activity, the effects of one of the compounds formed by this mechanism, 8-epi-prostaglandin F2 alpha, was examined in the kidney in the rat. Infusion of 8-epi-prostaglandin F2 alpha into a peripheral vein (5 micrograms/kg per min) or intrarenally (0.5-2.0 micrograms/kg per min) resulted in marked parallel reductions in renal blood flow and glomerular filtration rate. That the formation of these prostanoids is catalyzed by free radicals and that they can exert potent biological activity suggest that these prostanoids may participate as pathophysiological mediators in oxidant injury. Quantification of these compounds may also provide a noninvasive approach to assess oxidant status in humans. That the formation of these prostanoids occurs independent of the catalytic activity of the cyclooxygenase enzyme suggests that there may be limitations at times regarding the reliability of the use of cyclooxygenase inhibitors to assess the role of prostaglandins in certain pathophysiological processes.
Morrow
J D
JD
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6602.
Hill
K E
KE
Burk
R F
RF
Nammour
T M
TM
Badr
K F
KF
Roberts
L J
LJ
D000818:Animals; D015237:Dinoprost / Q000097:blood* / Q000302:isolation & purification / Q000652:urine; D004178:Diquat / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D013058:Mass Spectrometry; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D012643:Selenium / Q000172:deficiency; D013237:Stereoisomerism
D005609:Free Radicals; D004178:Diquat; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D012643:Selenium