Anthony Masliulo John Jav Colleoe o f criminal Justice The City University of New York New York, 10010
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The term prostaglandin was first applied in 1935 to lipid soluble, acidic substances isolated from seminal plasma which caused the contraction of smooth muscle and an increase in hlood pressure (1-3). Subsequent investigators have shown that prostaglandins are present in minute amounts in most of the tissues of mammals. To date some sixteen naturally occurring prostaglandins have been identified, and their structures established.
I1
I
n---r--l---l?--
rrosTagIanam
8, 11, 14
-
Eicosatrienoic acid
Structure and Synthesis Prostaglandins are Czo oxygenated, cyclic fatty acids derived in nature from the corresponding polyunsaturated fatty acids. There are six primary prostaglandins (Fig. 1) from which the remainder are presumably derived ( 4 ) . The enzymes involved in their hiosynthesis are associated with the microsomal fraction of cells (microsomal synthetase system).
8, 11, 14
OHH
-
Eicosatrienoic acid
H
,OH
OH
COOH
0 H
COOH
OH
PGE, C
C
5 ; 8, 11, 14
?HH
-
PGF,.
O
O
-
H
Eicosatetraenoic acid
H
-
COOH +
OH^
0 H
PGE,
5, 8, 11, 14, 17
PGF,,
-
-
Eicosapentaenoic acid
+ PGE,
PGE, Figure 2. Formation of prostaglandin by oxidative closure
The prostaglandins are placed in categories such as E, F, A and B according to the type of functional group present, and the number and location of double bonds (Fig. 1). The five-membered oxygenated ring is produced by the oxidative closure of the parent polyunsaturated fatty acid. The oxygen functions are introduced at positions 9 and 11, with concomitant closure a t positions 8 and 12 (Fig. 2). All of the oxygens in PGEI are derived from molecular oxygen. Although the structure of prostaglandins indicate the possibili& of stereoisomerism, only one isomer of each tvue .. has thus far heen isolated from mammahan tissues. Chemical synthesis of the primary prostaglandins has been accomplished by several investigators. The availahility of synthetic prostaglandins has made it possible for many scientists to explore the many interesting biological properties of these compounds. Metabolism Studies involving the in-vivo metabolism of prostaglandins in man indicate that several enzyme systems are involved in their catabolism. When PGEz is injected intravenously into human subjects, most of it is recovered in the urine. The remainder is converted to 7-hydroxy-5,11diketotetranorprosta-1,16-dioicacid by the following ordered sequence of transformations (5): (1) 15-OH-dehydrogenase, which is associated with the particle-free fraction of tissue homogenates, produces the keto group a t position 15. (2) A13-reductase, also associated with the particle-free fraction of tissue homogenates, removes the unsaturation a t position 13 in PGE2. (3) Beta ((3) and omega ( o ) oxidation systems, associated with the mitochondrial and microsomal fractions, respectively, produce the alterations shown in Figure 3. Extraction, Separation, and Quantitation Briefly, tissue homogenates or body fluids are extracted with chloroforn-ethanol (1:1), filtered, and the filtrate is evaporated to dryness in uacuo. The prostaglandins are then separated and purified chromatographically by the use of silicic acid columns, or by thin layer chromatography (tlc) on silver nitrate-impregnated Silica Gel. Since prostaglandins are present in nanogram (1 ng = 10-9 g) or subnanogram quantities in some body fluids (e.g., plasma), very sensitive methods are required for
eCO OHH
H
;OH
~ H H
PGF3. Figure 1. The six primary prostaglandins and their precursors.
602 / Journal of Chemical Education
T
AL3-reductase o-oxidation 15-OH-dehydrogensse
Figure 3. Conversion of PGEl l a 7-hydroxy-5.11-diketoletranarprosta1.18-dioic acid in man ( 5 )
their quantitation in such specimens. A sensitive assay utilizing the enzyme A's-reductase has been described, which reportedly can detect as little as 0.3 ng of prostaglandin (6). Methods combining gas liquid chromatography (glc) and mass spectrometry have also been described for the detection and quantitation of nanogram amounts of prostaglandins. Biological Role of Prostaglandins
As indicated earlier, prostaglandins mediate the contraction of smooth muscle. Small amounts of intravenously administered prostaglandin can induce labor or ahortions in late or early pregnancies, respectively. Since prostaglandins are naturally occurring substances, complications and side effects have been minimal in such applications. Some scientists believe that prostaglandins may prove to be ideal chemical contraceptives-only time will tell if this is indeed the case. Prostaglandins have been shown to modify the levels of 3'-5' cyclic adenosine monophosphate (cyclic AMP) in many tissues (7). Cyclic AMP is known, among other things, to expedite the mobilization of lipids by sympathetic nerve activation. This mobilization is blocked by the presence of minute amounts of PGEI which, presum-
ably inhibits the formation of cyclic AMP (8, 9). PGEl and PGEz have been demonstrated to modulate the function of tissues innervated by the sympathetic nervous system both in uitro and in uiuo (10). Strangely enough, prosta&andins have been shown, in some cases, to behave differentlv in uiuo and in uitro. For example, although progesterone synthesis is increased when isolated luteal tissue is incubated with prostaglandins in uitro (11, 13, the opposite effect is observed in uiuo (13, 14). Similarly, a stimulatory effect on thyroid and adrenal cortex is noted in uitro, and the opposite effect in uiuo (15, 16). The reasons for this a u ~ a r e n t l v anomalous behavior is unknown a t the present time: Recent studies (17) indicate that prostaglandins are somehow involved in the phenomenon of inflammation. Increased permeabilitv of ca~illaries. and mimation of polymorph~nuclearle&ocytes'can he'induced Gy prostaglandins. There is evidence indicating that the antiinflammatory effect of aspirin may he attributable to its ability to inhibit prostaglandin synthesis (18). Some scientists believe that prostaglandins, by virtue of their control of cyclic AMP levels, play an important role in RNA, protein and even DNA synthesis. Whether or not this proves to he the case, prostaglandins may prove to be some of the most important compounds discovered in this century. Literature Cited Euler. U. S.von..J PhwioL. 88, 213119361. Eulor. U. S, van.. Skond. Arch. Physioi.. 81.65(19391. Goldblatt. M.W.,J.Physioi.. 84.208(19351. Anderson.N..Ann. N Y A c o d Sci., 180. 14119711. Samuelron. B.. Grsn&m. E.. Green. K.. and Hamberg. M., Ann. N.Y. Acod. S c i . 180.138(19711. (61 Anaard. E., Mafrchinaky, F. M.,and SamueImn, B.. Seienm, 163,479 (19691. (71 Sham J.. Gibson, W.. Jessug, S., and Ramwell, P., Ann. N Y Acad. Sei., 180.241
(11 (21 131 I41 151
(19711 ,...., .
Butcher. R. W.. Ho. R. J.. Meng, H. C.. and Suthedand. E. W.. J. B i d Chsm.. 240.4515 119651. ButchecR. W., andSu1hedsnd.E. W..Ann N.Y. Acod Sei.. 139.849119671. Hedgvlst. P..Ann. N Y A c a d . Sci., 180.410(19711. Phsrriss, B. B.. Wyngarden, L. J., and Guthecht. G. D., in -Gonadotropins: ( E d i f o r : h n b e g , E.l,Gemn-X,Ine., LaaAltm, Caliomia, 1sEa.p. 121. Spemft L.. and Ramwell, P. W.. J. Ciin. Endoc,. Met.. 30.345 (19701. Gutknecht. G. D.,Carnefte, J. C.. and Pharriss. B. B.. B i d Reprod.. 1. 367 ((9f91 ,. ...,.
(141 Kirton. K. T.. Pharriss. 8. B.. and Forks. A. D.. Pme. Sor E m B i d M d 133.
Volume 50, Number 9, September 7973 / 603
