Chapter 14
A Perspective on Palytoxin Gary Strichartz
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Anesthesia Research Laboratories, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 A s one o f the most potent lethal toxins known, palytoxin (PTX) has attracted attention from a broad range o f investigators (1). T h e varieties o f physiological and biochemical effects o f these non-protein toxins (mw 2659-2677) from the genus (Coelenterata) palythoa provide a dizzying choice o f toxic mechanisms. A l m o s t all mammalian tissues or cells studied so far respond to P T X (2). T h e reported effects range from membrane depolarization (3-10), increased Na (11,12) and Ca influx (13), K efflux (11,14-16), stimulation o f arachidonic acid release [through deesterification o f membrane lipids (2)], stimulation or induction o f neurotransmitter (norepinephrine) release (13,17), inhibition o f Na /K -ATPase (10,11,14,18), induct i o n or stimulation o f contraction o f smooth muscle (3,13,17-19), p r o m o t i o n o f actions o f tumor-producing compounds (20), inhibition o f action o f growth-related factors (27) (by down regulation o f their specific membrane receptors), and erythrocyte haemolysis (22). A s is our tendency, we molecular pharmacologists are attempting to identify one primary action o f PTX that is c o m m o n to all o f these eventual effects. However, that task is confounded by several uncontrolled variables. First, i n few o f the experiments is a range o f P T X concentrations greater than l0 -fold carefully examined. This approach may be acceptable i n those cases where a single receptor o f defined affinity can be identified, but it fails i n the case o f compounds like P T X for which effects are reported from 10 M [inhibition o f binding o f epidermal growth factor (27)] to 10 M [enhancement o f Ca influx i n PC12 cells (13)]. Second, the time-course o f the assays are often o f different dimensions; depolarizations and i o n fluxes are measured i n fractions o f minutes, while tumor p r o m o t i o n or receptor regulation may take tens o f minutes to hours. T h i r d , the pharmacological specificity is almost never tested by the same criteria i n different assays. F o r example, N a flux and cellular depolarization by P T X are often subjected to tests for inhibition by ouabain, since H a b e r m a n n and colleagues showed that these responses were sensitive to cardiac glycosides [(14) but not to their aglycones], suggesting an action through the N a / K A T P a s e . B u t experimentalists testing other effects rarely conduct this assay, although they often propose an increase i n N a influx as a possible step i n the final effect (e.g., ref. 21). E v e n when this test is included, the results may appear contradictory; a fast-responding contraction o f the vas deferens to P T X was abolished by ouabain, whereas a slower responding contraction was potentiated (13,18). A l t h o u g h separate actions o f P T X o n smooth muscle and o n nerve, respectively, are posited to underly these two phases, the details o f the mechanisms remain obscure. O n e fact does emerge from the assembled literature, despite its disarray. Palytoxin does not appear to act by binding to one single cellular component to trigger a cascade o f responses. O r i g i n a l speculations that it might activate voltage+
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0097-6156/90/0418-0202S06.00/0 o 1990 American Chemical Society
Hall and Strichartz; Marine Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1990.
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A Perspective on Palytoxin
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gated N a channels seem to be disproven by its insensitivity to that channel's high affinity blocker, tetrodotoxin (4,10,13). A t this time the actions o f palytoxin o n cellular responses is complex, and the overall response may depend strongly o n the toxin's concentration and the time over which the assay is conducted. Parallel conclusions probably h o l d for the toxic responses o f organisms. Different tissues may contribute differentially to the final lethality (or its prevention), dependent o n the dose and the course o f toxin distribut i o n among the sensitive organs. A rational approach to identifying the lethal actions o f P T X requires knowledge o f each affected organ's acute and long-term sensitivity and its ability to recover normal function, as well as the biochemical and physiological responses o f tissues and individual cells.
Literature Cited 1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Kaul, P.N.; Farmer, M.R.; Ciereszko, L.S. Proc. West. Pharmacol. Soc. 1974, 17, 294. Levine, L.; Fujiki, H.; Gjika, H.B.; Van Vunakis, H. This volume, chapter 17. Deguchi, T.; Urakawa, N.; Takamatsu, S. Animal, Plant Microbial Toxins 1976, 2, 379. Dubois, J.M.; Cohen, J.B. J. Pharmac. Exp. Therap. 1977, 201, 148. Kudo, Y.; Shibata, S. Br. J. Pharmacol. 1980, 71, 575. Muramatsu, I.; Uemura, D.; Fujiwara, M.; Narahashi, T. J. Pharmacol. Exp. Therap. 1984, 231, 488. Sauviat, M.P.; Pater, C.; Berton, J. Toxicon 1987, 25, 695. Tesseraux, I.; Harris, J.B.; Watkins, S.C. In Toxins as Tools in Neurochemistry; Hucho, F., Ovchinnikov, Y.A., Eds.; Walter de Gruyter and Company, 1983; p. 91. Weidmann, S. Experimentia 1977, 33, 1487. Castle, N.A.; Strichartz, G.R. Toxicon 1988, 10, 941. Chhatawal, G.S.; Hessler, H.-J.; Habermann, E. Naunyn-Schmiedeberg's Archs. Pharmac. 1983, 319, 101. Muramatsu, I.; Nishio, M.; Uemura, D. J. Pharmacobio. Dyn. 1987, 10, S-113. Ohizumi, Y. This volume, chapter 16. Bottinger, H.; Beress, L.; Habermann, E. Biochim. Biophys. Acta 1986, 861, 165. Chhatwal, G.S.; Hessler, H.J.; Habermann, E. Naunyn-Schmiedelbergs Arch. Pharmacol. 1983, 323, 261-268. Maramatsu, I.; Nishio, M.; Kigoshi, S.; Uemura, D. Br. J. Pharmacol. 1988, 93, 811-816. Ishida, Y.; Kajiwara, A.; Takagi, K.; Ohizumi, Y.; Shibata, S.J.Pharmacol. Exp. Therap. 1985a, 232, 551. Ishida, Y.; Satake, N.; Habon, J.; Kitano, H.; Shibata, S. J. Pharmacol. Exp. Therap. 1985b, 232, 557. Ito, K.; Karaki, H.; Ishida, Y.; Urakawa, N.; Deguchi, T. Jon. IJ. Pharmacol. 1976, 26, 683. Fujiki, H.; Suganuma, M.; Nakayasu, M.; Hakii, H.; Horiuchi, R.; Takayama, S.; Sugimura, T. Carcinogenesis 1986, 7, 707-710. Wattenberg, E.V.; Fujiki, H.; Rosner, M.R. This volume, chapter 15. Habermann, E.; Ahnert-Hilger, G.; Chhatwal, G.S.; Beress, L. Biochim. Biophys. Acta 1981a, 649, 481-486.
RECEIVED May 4, 1989
Hall and Strichartz; Marine Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1990.
