Chapter 25
Some Natural Jellyfish Toxins
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Joseph W. Burnett Division of Dermatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 Recent investigations on natural jellyfish toxins have centered upon four species. The four animals studied most are: Chrysaora quinquecirrha (sea nettle), whose distribution is worldwide, appears seasonally in the Chesapeake Bay; Physalia physalis (Portuguese man-o'war) has a worldwide distribution with an annual occurrence in the southeast American, Atlantic, and Gulf Coasts; Chironex fleckeri (box jellyfish) is found in the northeast Australian and Indo Pacific areas; and Pelagia noctiluca (mauve baubler), whose distribution is also worldwide, can be abundant in the Mediterranean Sea. All of these animals deliver their venom by means of an intracellular organelle, the nematocyst, which everts a toxin-coated thread forcefully to penetrate into the human dermis. The human reactions to the natural jellyfish toxins can be classified as fatal, systemic, chronic, or local (1) (Table I). Death can be produced by toxicity in a dose dependent manner through cardiotoxic, central respiratory, or renal effects. Anaphylaxis has been reported in a limited number of cases. The systemic reactions include a spontaneously remitting syndrome produced by Carukia barnesi called "Irukandji", which is characterized by muscle cramps, nausea, vomiting, tachycardia, and hypertension lasting for two days. Local reactions to envenomation include persistent eruptions, recurrent eruptions, eruptions distant to the site of envenomation, exaggerated local angioedema, papular urticaria, and respiratory acidosis. Chronic lesions such as keloids, pigmentation, fat atrophy, contractions, gangrene with vascular spasm, mononeuritis, autonomic nerve paralysis, urticaria, and bladder paralysis with ataxia occur.
Preparation of Venoms and Toxins The methods of preparing the purified venom extracts vary according to the species. Presently Chrysaora quinquecirrha nematocysts are isolated by grinding, passage through a mesh, and centrifugation before being ruptured by sonic treatment. Organelles from Chironex flecked are prepared by homogenization and centrifugation or the venom is taken from a beaker which has been covered by a monolayer of amnion cells on top of which tentacles have been placed, moved, and electrically stimulated (2). Recently Physalia nematocysts have been purified by fluorescent automated cell sorters (FACS) into two sizes (3). Because of their stability, Physalia are the only species whose nematocysts have been purified in this manner. A problem with this technique is that discharged nematocysts with their long threads still attached to the capsule can disturb the size sorting of the organelles. The best method of preparing individual toxins from the crude venom is by affinity immunochromatography utilizing monoclonal antibody or in one instance, polyclonal antibody (4-6). Monoclonal antibodies to both the fishing and mesentery
0097-6156/90/0418-0333S06.00/0 o 1990 American Chemical Society
In Marine Toxins; Hall, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.
MARINE TOXINS: ORIGIN, STRUCTURE, AND MOLECULAR PHARMACOLOGY
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Table I. Important Disorders Produced by Jellyfish Envenomation
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Acute local reactions E r u p t i o n and pain due to toxin Exaggerated local angioedema Delayed reactions up to several hours Recurrent eruptions up to 4 episodes Distant site reactions Papular urticaria Respiratory acidosis
Post episode dermatoses Herpes simplex G r a n u l o m a annulare
Chronic reactions Keloids Pigmentation Fat atrophy Contractions Gangrene, vascular spasm Mononeuritis A u t o n o m i c nerve paralysis Urticaria fl
Fatal reactions 1. Toxin-induced Immediate cardiac arrest R a p i d respiratory arrest Later "shocked" kidney 2. Anaphylaxis
a
Two of these patients had operative repair of their vasospasm and both developed postoperative fever of 102 ° F .
tentacles o f Chrysaora quinquecirrha have been prepared and yield toxins o f 100,000 and 190,000 o r 108,000, 160,000, and 175,000, respectively, for the fishing and mesentery tentacles. Earlier experiments utilizing i o n exchange columns and molecular sieving techniques yielded a toxin o f 240,000 molecular weight for Physalia physalis (7). However, m o n o c l o n a l antibody immunoaffinity columns inoculated with the contents o f F A C S purified Physalia nematocysts yielded a toxin o f 69,000 molecular weight (3). Past experiments w i t h Chironex using i o n exchange and gel filtration chromatography have yielded toxins with molecular weights o f 10,000 to 30,000, 75,000, 150,000 and 500,000 (2,8). Toxins i n the 50,000 and 150,000 molecular weight range were obtained by immunoaffinity chromatography with polyclonal antisera (6). M o n o c l o n a l antibody columns separated Chironex toxins near 20,000 as well as other sizes (9). These results indicate that the venom within Chironex nematocysts contains a mixture o f individual toxins with varying potency and activities.
Human Reactions to the Toxins A l l the jellyfish venoms are toxic but also stimulate the cell mediated and h u m o r a l i m m u n o l o g i c a l systems o f man. After injection o f large doses o f jellyfish venom into h u m a n skin, a perivascular mononuclear cell infiltration appears w i t h i n the dermis. This infiltration is composed predominantly o f helper inducer cells which produce suppressor activity. It appears that the N K enhancement o f human leukocytes i n patients envenomated by Chrysaora quinquecirrha is depressed when the c l i n ical lesion is inflammatory (10). Recovery from this suppression follows the amelioration o f the acute cutaneous reaction. In other instances, envenomated patients have abnormal macrophage migration tests (11). P a i n production is the most c o m m o n injury inflicted o n man. This noxious stimulus is perceived almost instantly after skin - tentacle contact. A subpopulation (30 - 40%) o f visceral sensory C fibers denoting noscioception have been shown to be selectively excited experimentally i n nerve ganglia preparations by a component o f
In Marine Toxins; Hall, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.
25. BURNETT
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Natural Jellyfish Toxins
Physalia nematocyst toxin (22). This phenomenon appears to be important in understanding the pathogenesis of toxin-induced cutaneous pain. Additionally, the importance of kinin-like mediators in pain production has also been hypothesized (2). The toxic mechanism of action of these various jellyfish venoms is complex. The cardiotoxic reaction seems to focus on calcium transport and is blocked by the prior or post administration of therapeutic doses of verapamil (13). In neuronal tissue, Chrysaora venom induces large cationic selective channels which open and close spontaneously. These channels are permeable to Na , Li , K and Cs but not Ca , and the channels are present in spite of the treatment with sodium and potassium inhibitors such as tetrodotoxin and tetraethylammonium (14). +
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Summary Research on the chemistry, toxicology, immunology, and treatment of jellyfish venoms has been progressing steadily for the past 20 years. In spite of this fact, knowledge of these venoms and their activity is not as complete as that of other species. The reasons for this statement are: (1) some animals are not abundant and are found in isolated marine areas; (2) the venoms are thermolabile and appear to adhere to support media and to have a tendency to aggregate or dissociate; (3) interesting or unusual clinical cases are poorly reported, difficult to find, and occur in sparsely populated areas of the world. In addition it appears that each species has a venom with its own particular characteristics. Although there are some general common relationships between these venoms, it is apparent that both the first aid and definitive therapies of envenomation by jellyfish will be species specific to some degree. It is hoped that additional interest will result in better case reporting and further research both by biologists and physicians.
Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Burnett, J.W.; Calton, G.J.; Burnett, H.W. J. Amer. Acad. Dermatol. 1986, 14, 100-106. Burnett J.W.; Calton G.J. Toxicon 1987, 25, 581-602. Burnett, J.W.; Ordonez, J.V.; Calton, G.J. Toxicon 1986, 24, 514-518. Cobbs, C.S.; Gaur, P.K.; Russo, A.J.; Warnick, J.E.; Calton, G.J.; Burnett, J.W. Toxicon 1983, 21. 385-391. Kelman, S.N.; Calton, G.J.; Burnett, J.W. Toxicon 1984, 22, 139-144. Calton, G.J.; Burnett, J.W. Toxicon 1986, 24, 416-420. Tamkun, M.M.; Hessinger, D.; Hessinger, D. Biochim. Biophys. Acta. 1981, 667, 87-92. Olson, C.E.; Pockl, E.E.; Calton, G.J.; Burnett, J.W. Toxicon 1984, 22, 733-742. Naguib, A.M.F.; Bonsal, J.; Calton, G.J.; Burnett, J.W. Toxicon 1988, 26, 387-394. Burnett, J.W.; Hepper, K.P.; Aurelian, L.; Calton, G.J.; Gardepe, S.F. J. Amer. Acad. Dermatol. 1987, 17, 86-92. Burnett. J.W.; Hepper, K.P.; Aurelian, L. Toxicon 1986, 24, 104-107. Weinrich D.; Burnett, J.W.; unpublished data. Burnett, J.W.; Calton, G.J. Med. J. Aust. 1983, 2, 192-194. Dubois, J.M.; Tanguy, J.; Burnett, J.W. Biophysics J. 1983, 42, 199-202.
RECEIVED
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9,
1989
In Marine Toxins; Hall, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.
