The occurrence of prostaglandins and related compounds in lower organisms

PROSTAGLANDINSLEUKOTRIENES AND ESSENTIALFATTYACIDS ProstaglandinsLeukotrienesand EssentialFatty Acids (1995) 52, 357-364 © Pearson ProfessionalLtd 1995

REVIEW The Occurrence of Prostaglandins and Related Compounds in Lower Organisms M. Lama~ka and J. Sajbidor Department of Biochemical Technology, Chemical Faculty, Slovak Technical University, Radlinskgho 9, 812 37 Bratislava, Slovak Republic (Reprint requests to JS)

reviews dealing with this subject (6-9). Although there are many investigations describing the biological effects of eicosanoids on higher vertebrates, only very little is known about their physiological significance in lower organisms. The analytical chemistry of eicosanoids is a big problem and the reliability of any presented results and conclusions strongly depends on the methodology used. Therefore, we briefly mention the analytical methods in some of the papers reviewed, especially the older ones.

INTRODUCTION It is well known that prostaglandins (PGs) and related substances (also known as eicosanoids) are involved in a variety of clinically important processes, including inflammation, fever, thrombosis, allergic and immune responses (1). Although some of these compounds are already used as drugs, their full pharmaceutical potential has yet to be realized (2-4). For a long time PGs and related substances were reported only in higher vertebrates (5). Later, many lower animals (6, 7), plants (8, 9) and microorganisms (10) were found to be able to convert exogenous or endogenous polyunsaturated fatty acids (PUFAs) to various eicosanoids. There are at least three reasons why one should search for new sources of eicosanoids. Firstly, these substances are extremely costly because complex chemical syntheses are necessary for their manufacture. Finding new sources could lower their prices and make them available for broader/ise both in research and therapeutics. For example, there'Js a possibility of biotechnological production of eicosanoids using suitable microorganisms or macroscopic algae. Secondly, many eicosanoids are biologically active in very small amounts. If they reach the human body (e.g. by infection with microorganisms that produce them or by ingestion of food that contains large quantities) this may have serious consequences. 'Ogonori' poisoning may be an example of this (11). Finally, by searching for new sources and new eicosanoids it is possible that suitable models for studying their biochemistry may be found. The present survey summarizes information about the occurrence and physiological effect of PGs and related compounds in lower organisms, with emphasis on microorganisms. Plants and other lower organisms are only briefly mentioned, because there are already several

BACTERIA There are only a few reports dealing with the presence of eicosanoids in bacteria and no attempt has been made to understand their physiological role. The ability of various bacteria to synthesize eicosanoids is summarized in Table 1. Beal et al (12) and Colbert (13) reported bioconTable 1 The ability o f various bacteria to synthesize eicosanoids de n o v o or f r o m fatty acid precursors Bacteria

G*/G -

Eicosanoid

Ref.

G÷ G~ G÷ G+ G÷ GG+

Various P G s a n d P G like substances d e p e n d i n g on the P U F A u s e d for the transformation * P G A , E, F and P G like substances *PGE2-1ike substances

15-18

G-

P G E 2 a n d PGF2c~

19

G÷

PGA2, PGB2, PGE2, PGFz~

22, 23

Bacteria b e l o n g i n g to

Mycobacterium Pseudomonas Micrococcus Streptomyces Nocardia Pseudomonas aeruginosa Propionibacterium aches Acinetobacter calcoaceticus Actinomyces spheroides *De n o v o synthesis. 357

12

12, 14

358

Prostaglandins Leukotrienes and Essential Fatty Acids

version of arachidonic acid (AA, 20:4, m-6) to PGFI~, PGE2,,, PGEI and PGE2 by the growing culture of some species of the genera Pseudomonas, Mycobacterium and Micrococcus. This transformation was monitored by combining paper strip chromatography and biological assays. Unfortunately, no yields were mentioned. Skarnes and Howard (14) reported that Pseudomonas aeruginosa was capable of synthesizing PGA, PGE and PGF or PG-like substances by aerobic pathways in nanogram amounts. PGs were identified by thin layer chromatography (TLC) and radioimmunoassay (RIA) methods. Since the medium was free of PUFA precursors, these substances were apparently synthesized de novo. Abrahamsson et al (15) searched for some inflammatory agents in Propionibacterium acnes. After extraction and purification of lipids they detected a fraction co-migrating in TLC with authentic PGE2 standard. Further analysis (high-performance liquid chromatography (HPLC), mass spectroscopy (MS) and bioassay) revealed that this unknown compound was a vasoactive substance with the aliphatic chain of the PG family, but different from PGE2 (16, 17). Later the presence of PGE2-1ike material in some, but not all, isolates of P. acnes was confirmed (18). Another bacterium that was able to transform AA to PGE2 and PGF2~ is Acinetobacter calcoaceticus (19). In 1979 Gulbis et al (20) reported that various bacteria produced and released PGE 2 and PGF2a into the medium in the presence of exogenous AA. This observation was later re-evaluated, because it had been shown that the apparent production of PGs by these bacteria may be explained by PGE2 contamination and AA autooxidation (10, 18). It should be mentioned that the possibility of nonenzymatic conversion of eicosapolyenoic fatty acids to PGs was also demonstrated by Nugteren et al (21). The authors concluded their study with the statement that the production of PGE2 does not occur in common bacteria (Escherichia coli, Enterobacter, Klebsiela Table 2

pneumoniae, Proteus mirabilis, Staphylococcus epidermis and Staphylococcus aureus). In some species of filamentous bacteria (Streptomyces and Nocardia) (12, 22, 23), the reported conversion of AA of PGs by Actinomyces spheroides was about 40% and the molar ratio of PGs produced was approximately 10.6 : 2.8 : 1.5 : 0.9 for PGFzc~ : PGE 2 : PGA 2 : PGB2. The products of AA incubation with the microsomal actinomyces protein were examined by ultraviolet (UV)-spectrometry, TLC and Magnus' method (22, 23). It is interesting that up to the present time only one report of lipoxygenase activity in a prokaryote has been published (24). The enzyme has been isolated from a cyanobacterium (the authors refer to their organism as 'the green alga Oscillatoria') which converted linoleic acid into biologically active 13-hydroperoxylinoleic and 9-hydroperoxylinoleic acids (24).

YEASTS AND YEAST-LIKE MICROORGANISMS Although the lipoxygenase activity in Saccharomyces cerevisiae was reported in 1983 (25), the first reports of the occurrence of some eicosanoids in yeasts and yeast-like organisms were published only recently (see Table 2). Kock et al (26), indicated the presence of significant quantities of PGFza in Lipomycetaceae (33 strains) and Saccharomyces cerevisiae. The concentration of PGF2~, determined by RIA, ranged from 450 pg/g (Lipomyces starkeyi) to 4200 pg/g dry weight of yeast biomass (Zygozyma oligophaga). The authors, however, warn that the RIA results should be treated with caution because of possible cross-reactivity with structurally related compounds. Such reactions may result in overestimates of the amount of PG present (26). Dipodascopsis uninucleata is another species of

The ability of various fungi to synthesize eicosanoids de novo or from fatty acid

precursors Fungi

Saccharomyces cerevisiae Lipomycetaceae 33 strains Dipodascopsis uninucleata Dipodascopsis tdthii Various fungi belonging to

Ascomycetes, Phycomycetes, Basidiomycetes, Deuteromycetes Fusarium sambucinum Trichothecium roseum Aspergillus sp. Mortierella sp. Saprolegnia parasitica Gauemannomyces graminis *De novo synthesis.

Eicosanoid

Ref. 26, 29

*PGF2a PGF2a, isomers of c~-pentanor-PGFzccT-lactone, 3-HETE PGE2, PGF2c~, other aspirin sensitive metabolites various PGs depending on the PUFA (AA, EPA or DHGLA) employed for the transformation

26,28,32,33,49,50 32,52

12

PGE2 and PGF2~ PGE 2 and PGF2a PGE 2 and PGF2c~

53, 55, 56 53, 55 19

trihydroxyeicosatrienoic acids (18R)-HETE, (19R)-HETE, 17,18-DiHETE

64 58, 60

Prostaglandinsin LowerOrganisms 359

Lipomycetaceae that can be considered as a prospective PG producer. The extracts of this yeast-like organism inhibited the aggregation of platelets induced by either ADP or collagen in human platelet-rich plasma. Since PGE1, PGD2 and PGI2 are strong inhibitors of platelet aggregation (27), their presence in cells or growth medium could be expected. When radiolabelled AA was added to growing cells of Dipodascopsis uninucleata, two isomers of prostacyclin (PGI2) metabolites, c~pentanor-PGF2a-y-lactone together with 3-hydroxy5,8,11,14-eicosatetraenoic acid (3-HETE) were identified. Moreover, the formation of all these metabolites was inhibited by 1 mM acetylsalicylic acid, an inhibitor of the cyclooxygenase pathway in mammals (26, 2831). Besides D. uninucleata, D. t6thii and Lipomyces anomalus are capable of transforming exogenous AA into similar compounds (32). The formation of these substances was inhibited by acetylsalicylic acid and indomethacin (inhibitors of the cyclooxygenase pathway) and by nordihydroguaiaretic acid (inhibitor of both cyclooxygenase and lipoxygenase pathways). It is possible that the AA cascade is wholly operative in Dipodascopsis and is not solely dependent on the utilization of external sources of AA, since trace amounts of dihomo-y-linolenic acid (DHGLA, 20:3, n-6) and AA were identified in D. uninucleata (33, 34). It is a matter of debate, whether PGs in Lipomycetaceae are formed via the cyclooxygenase pathway as in mammals. The inhibitory effect of acetylsalicylic acid and indomethacin supports this hypothesis. But up to the present time, five different biosynthetic routes to a skeleton which is recognizably PG-like have been discovered (35): 1. prostaglandin H synthase in mammals (36, 37), 2. PG synthesis in the coral Plexaura homomalla (38, 39), 3. algal carbocyclic oxylipin biosynthesis (40-42), 4. brefeldin biosynthesis by Penicillium brefeIdianum (43), and 5. jasmonic acid and phytodienoic acid production by higher plants (44). Morrow et al (45, 46) reported another possibility. They found that, in humans, AA was transformed into PGF2-1ike substances (e.g. 8-epi-PGF2~), without the participation of cyclooxygenase, by radical-catalyzed peroxidation. Some attempts have been made to explain the physiological significance of PGs and related compounds in yeasts and yeast-like organisms. Studying the effect of exogenous fatty acids (FAs) on zygote formation in Saccharomyces cerevisiae, it was found that AA and oleic acid considerably stimulated zygote formation in the presence of mating pheromone (47). From this, it was proposed that AA may actively regulate this process. However, up to present time, no evidence exists that S. cerevisiae contains gamma-linolenic acid (GLA, 18:3, o)-6) or AA (48). According to Kock et al (26), these

substances may regulate the adenylate cyclase system, as in humans. A similar adenylate cyclase system, which is important for growth control and sexual reproduction, was discovered in S. cerevisiae (29). Acetylsalicylic acid and indomethacin inhibited the life cycles of Dipodascopsis uninucleata and D. t6thii and ascosporogenesis was the most susceptible phase (49). For a better understanding of the biological significance of AA metabolites, the distribution of these compounds in the life cycle of D. uninucleata was investigated (50). At first, the distribution of AA metabolites in synchronized cultures of D. uninucleata was observed and it was found that most PG-like metabolites were associated with ascospores and corresponding supernatants. As the asexual phase progressed, a down-regulation occurred in all these metabolites in both cells and supernatants. Almost no PGs or lipoxygenase products were observed for 5 h in the sexual phase, while 3HETE increased after a previous decrease during the hyphal formation. Similar results were obtained when AA was added at different stages of the life cycle. To verify that the AA cascade is mostly associated with ascospores, the authors separated ascospores from other vegetative cells and asci after non-synchronous cultures had been incubated in the presence of labelled AA. Again, most of the AA cascade activity was found in ascospores (50). Later it was also demonstrated that in D. uninucleata there was an apparent metabolic distinction between AA (potential precursor of PG-type metabolites) and oleic acid (presumably completely used as a functional fatty acyl group in phospholipids and triacylglycerols) (51). Experiments with D. t6thii revealed that PGE 2 and PGFzc~ are produced during ascosporogenesis (52). It was also demonstrated that a small yeast population density in liquid medium is essential for ascosporogenesis and PG production in this yeast. However, the PGs were identified only by using labeled AA as precursor, TLC and scintilation counting (48, 52).

OTHERFUNGI The first reports dealing with the transformation of exogenous PUFAs by Phycomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes to PGs and PG-like substances were presented by the Upjohn Company in 1966 (12, 13). Addition of AA to the growth medium of Fusarium sambucinum or Trichothecium roseum cultivated in a liquid medium resulted in the formation of PGE2 and PGF2~ (53-56). The degree of AA conversion to PGs and the ratio of PGF2~ to PGE2 formed depended on the growth phase when AA was added to the medium (55). Surprisingly, the formation of PGs by F. sambucinum was not inhibited by acetylsalicylic acid (56). Considering this result and on the basis of only one inhibition study (1.8 mg/1 concentration of acetylsalicylic acid was used)

360 ProstaglandinsLeukotrienesand EssentialFattyAcids the authors concluded that the synthesis of PGs in F.

sambucinum occurred by a different pathway than in mammals. However, this hypothesis was supported neither by testing higher concentrations of acetylsalicylic acid (180 mg/1 is commonly used) nor by using other inhibitors of cyclooxygenase. Aspergillus and Mortierella sp were reported to be able to transform eicosapolyenoic FAs (endogenous or exogenous) to PGs, and the process was patented (19). A role for PG or PG-like compounds in the development of Achlya caroliniana, Achlya ambisexualis and Saprolegnia parasitica was suggested, because aspirin and indomethacin inhibited the growth of these Oomycetes in a dose-related manner. This suggestion was supported by the observation that the addition of PGFI~ to the growth medium partially overcame the growth inhibition caused by indomethacin (57). In 1969 Sih et al (58) reported that the fungus Gaeumannomyces graminis (formerly Ophiobolus graminis) converted exogenous AA to 18-hydroxy5,8,11,14-(Z,Z,Z,Z)-eicosatetraenoic acid (18-HETE) and 19-hydroxy-5,8,11,14-(Z,Z,Z,Z)-eicosatetraenoic acid (19-HETE) in an overall yield of about 40%. This work is of recent interest because (19R)-HETE and (19S)HETE have different biological effects on blood vessels and on renal Na+/K+-ATPase (59). Brodowsky and Oliw (60) incubated cytosolic and microsomal fractions of G. graminis with various 14C-labelled unsaturated FAs. Linoleic acid (LA, 18:2 n-6) was metabolized mainly to (8R)-hydroxy-9,12-octadecadienoic acid and c~-linolenic acid (ALA, 18:3 n-3) was converted mainly to 8hydroxy-9,12,15-octadecatrienoic acid (8-HODE) and to a smaller amount of 15,16-diol. In contrast, 8-hydroxy metabolites of AA and eicosapentaenoic acid (EPA, 20:5 n-3) were not detected. AA was efficiently converted to (18R)- and (19R)-HETE and to traces of 17-HETE. EPA was metabolized mainly to 17,18 -diol (17,18 -DiHETE). The nature of the enzymes employed in the oxygenation of the FAs was not investigated, but the authors assume that the co2- and c03-hydroxylation and 0~3-epoxidation were catalyzed by cytochrome P-450. (8R)-HODE, which possesses antifungal activity, is formed from an intermediate hydroperoxide, (8R)-HPODE (61). Fungal lipoxygenase was isolated and characterized from Fusarium oxysporum (62, 63). The enzyme showed higher specificity for linoleate, which was transformed to 9- and 13-hydroperoxides. Eicosapolyenoic FAs were not tested. Lipoxygenase activity was also found in some strains belonging to Oomycetes, i.e. Saprolegnia parasitica (64-66) and Achlya ambisexualis (67). The articles dealing with the occurrence of PGs and PGs-like compounds in fungi are summarized in Table 2.

PROTOZOA Hokama et al (68) analysed the ethyl acetate/isopropanol

extract of 2.8 x 108 cells of Tetrahymena pyriformis. Using the RIA method and 41.3 mg of lipid, the molar ratio of PGE2, PGB and PGF2~ was found to be as follows - 62.8:34:2.7. Moreover, the authors examined the effect of acetylsalicylic acid on T. pyriformis. Acetylsalicylic acid inhibited (to 50%) the growth of a 24-h culture of T. pyriformis at a dose of approximately 200mg/1. The growth was completely inhibited at 600 mg/1. From these results it was suggested that PGs are important for the survival and propagation of this protozoon (68). The presence of PGF2 in Tetrahymena sp. was later confirmed by Csaba and Nagy (69). PGs were also detected in Entamoeba histolytica (70), and the ability to transform AA to PGs via the cyclooxygenase pathway was reported in both pathogenic and non-pathogenic isolates of the protozoan Acanthamoeba castellani (71, 72). An interesting attempt to understand the physiological significance of PGs in Amoeba proteus was made by Prusch et al (73). Phagocytosis in A. proteus was shown to be induced with either PGs or AA (73, 74). The induction of phagocytosis with AA could be partially inhibited by indomethacin and this inhibition could be reversed by the addition of PGE 2. The phagocytosis induced by a chemotactic peptide N-formylmethionylleucylphenylalanine was also partially inhibited by indomethacin. From these observations it was suggested that PGs or biochemically related substances, play a signal-coupling role during phagocytosis in the amoeba (73), but no further supporting experiments were carried out.

ALGAE The first reported occurrence of eicosanoids in algae appeared in 1979. From the aqueous extracts of the red alga Gracilaria lichenoides an anti-hypertensive agent was isolated (75). Further analysis (HPLC, NMR, MS) revealed that the bioactive substance was a mixture of PGE2 (0.05-0.07% of dry weight) and PGF2a (0.070.10% of dry weight). Similarly, in the extracts of Gracilaria verrucosa PGE2 and PGA2 were identified (11) and the method for extraction of PGE 2 from this alga was patented (76). Later, other patents describing the conversion of exogenous or endogenous PUFAs by enzymes of G. verrucosa to PGE1, PGE2, PGE3 and PGF2~ appeared (77, 78). PGE2, PGF2~ and other lipoxygenase products were found in the unicell Euglena gracilis by RIA techniques (79). As the production of these eicosanoids was greater in cells grown in the dark than those grown in the light, it has been suggested that their production may be the result of the organism' s animal-type metabolic capacities. Another unicellular alga, Chlorella pyrenoidosa, was reported to possess lipoxygenase activity (80). An unusual oxidized FA derivative, the novel tetracyclic prostanoid-like eicosanoid named hybrida-

Prostaglandins in Lower Organisms 361

lactone, was isolated from the red alga Laurencia hybrida (81, 82). After these few sporadic reports the systematic work in this field began and most of the research activity has been performed by the research group under the leadership of William Gerwick. Various red marine algae belonging to Rhodophyta are rich sources of eicosanoid-type natural products (0.1-5.0% of crude lipid extracts) (83). Different pharmacologically potent 'mammalian' AA metabolites, e.g. 12-HETE, 12-HEPE, (6E)-LTB4 and hepoxilin B 3, were isolated from Rhodophyta(Table 3). A few of these substances represent novel compounds never previously isolated from nature (e.g. (12R, 13S)-DiHETE and costanolactones). All of these algal metabolites could logically arise from initial metabolism by a 12lipoxygenase reaction, although this specific metabolic activity is unknown in the plant kingdom (83, 84). The authors suggested that this metabolism was important to physiological processes in red algae and they speculated that the eicosanoids may: 1. play a role in osmoregulation by modulating the activity of ATPase ion pumps, 2. mediate the synchronization of gamete development and release in red algae, 3. regulate plant growth and tissue development as jasmonic acid does in higher plants, and 4. be involved in a wound response, as it is believed some lipoxygenase products do in higher plants (83). These studies were later extended to the members of the Phaephyceae and Chlorophyta (85). In the Chlorophyta only the metabolism of 18-carbon FAs was observed, which was consistent with the overall profile of available PUFAs in these algae. C18 acids were initially oxidized by action of a lipoxygenase at C-9 or C-13. This positional specificity is the same as observed in the lipoxygenase from some higher plants and may Table 3

reflect the dual specificity of a single enzyme (86). In the Phaephyceaeproducts deriving from the metabolism of both C18 and C20 fatty acids have been observed, with the majority initially being oxidized at C-13 (~06) in the 18-carbon class and C-15 (co6) in the 20-carbon class (85). More detailed information about eicosanoids in algae is available (35, 85, 87, 88).

OTHER LOWER ORGANISMS

The occurrence of PGs and related substances in higher plants has been reviewed by Panossian (8, 9) and the effects of PGs on physiological and biochemical functions in plants were reviewed by Yurin (89). Although in plants the main substrates of lipoxygenases are C 18 fatty acids (LA or ALA), these enzymes can convert exogenous eicosapolyenoic FAs to various eicosanoids, e.g. PGs (90, 91), (5S)- and (SS)-hydroperoxides (92, 93), leukotrienes and leukotriene-like substances (92, 9496). For more detailed information see other reviews (86, 97). Marine organisms (mainly marine corals, molluscs and fish) represent another group of lower organisms where various unusual eicosanoids (e.g. clavulones, chlorovulones, claviridenones and punaglandins) were discovered. Several reviews dealing with marine eicosanoids and their physiological significance have been published (e.g. 6, 7, 35, 88, 98, 99).

CONCLUSIONS Various lower organisms (i.e. microorganisms, plants, invertebrates and lower vertebrates) have been reported to possess enzymes that are capable of synthesizing PGs

Occurrence of eicosanoids in algae (83)

Eicosanoid

Algae

PGE2, PGF2a

Euglena gracilis Gracilaria lichenoides Gracilaria verrucosa Laurencia hybrida Murrayella periclados Gracilariopsis lemaneiformis Platysiphonia miniata CottonielIa filamentosa Constantinea simplex Murrayella periclados Gracilariopsis lemaneiformis Constantinea simplex Murrayella periclados Platysiphonia miniata CottonielIa filamentosa Farlowia molis Gracilariopsis lemaneiformis Constantinea simplex Constantinea simplex Laminaria sinclairii L. setchelii L. saccharina

Hybridalactone (12S)-HETE

(12S)-HEPE (6E)-LTB4, ethyl ester Hepoxilin B3 (12R, 13S)-DiHETE and (12R, 13S)-DiHEPE Constanolactone A and B (15S)-HETE and (15S)-HEPE

Ref. 11,75, 77, 79 81, 82 83-85, 100

83, 85, 101, 102 83 83, 103 83, 85, 102 85, 104 85

362

Prostaglandins Leukotrienes and Essential Fatty Acids

or related substances. According to their ability to synthesize eicosanoids de novo, these organisms can be divided into two groups. The first group is capable of producing eicosanoids from endogenous precursors (eicosapolyenoic FAs) and members of this group (e.g. marine corals and macroscopic algae belonging to Rhodophyta) may serve as a source of these valuable biochemicals. The organisms of the second group do not produce eicosanoids in natural conditions because they do not synthesize eicosapolyenoic acids. The main substrates of oxygenases in these organisms are other unsaturated FAs (e.g. LA or ALA); however, many of them were found to be able to convert exogenous PUFAs to PGs or related substances. Organisms belonging to this group (e.g. most plants and microorganisms) or enzymes isolated from their body can be used in the manufacture of eicosanoids from various PUFAs by bioconversion. The physiological role of eicosanoids in lower organisms, especially in microorganisms, is unknown. Some attempts have been made to understand the significance of these substances for yeast-like organisms. It is suggested that AA metabolites are of vital significance for Dipodascopsis species, most of them being produced during ascosporogenesis. It is possible that these compounds regulate the adenylate cyclase system, as in humans. Since the red marine algae (Rhodophyta) are a very rich source of eicosanoids, these metabolites are probably important to physiological processes in these organisms. References 1. Pinsker P. Ikosanoids in internal medicine. Health service P. H., Praha, Avicenum, 1990. 2. Slater T F, McDonald-Gibson R G. Introduction to the eicosanoids. In: Benedetto C, McDonald-Gibson R G, Nigam S, Slater T F, eds. Prostaglandins and related substances - a practical approach. Oxford: IRL Press, 1987: 1-5. 3. Holland H L, Brown F M, Rao J A, Chenchaiah P C. Synthetic approaches to the prostaglandins using microbial biotransformation. Dev Ind Microbiol (J Ind Microbiol Suppl 3) 1988; 29: 191-195. 4. Baker R R. The eicosanoids: A historical overview. Clinical Biochemistry 1990; 23: 455-458. 5. Sigal E. The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol 1991; 260: L13-L28. 6. Nomura T, Ogata H. Distribution of prostaglandins in the animal kingdom. Biochim Biophys Acta 1976; 431: 127-131. 7. Ogata H, Nomura T, Hata M. Prostaglandin biosynthesis in the tissue homogenates of marine animals. Nippon Suisan Gakkaishi 1978; 44: 1367-1370. 8. Panossian A G. Search for prostaglandins and substances related to them in plants. Rastitel'nyje Resursy 1986; 22: 441-449. 9. Panossian A G. Search for prostaglandins and related compounds in plants. Prostaglandins 1987; 33: 363-381. 10. Milman I A, Freimanis J F. Microbiological synthesis and transformation of prostaglandins. Prildadnaja Biochim Mikrobiol 1986; 22: 595-606. 11. Fusetani N, Hashimoto K. Prostaglandin E2: a candidate for causative agent of 'Ogonori' poisoning. Nippon Suisan Gakkaishi 1984; 50: 465-469.

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