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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 273, Issue 4, pp 313–330 | Cite as

Biochemistry and pharmacology of the crotoxin complex

II. Possible interrelationships between toxicity and organ distribution of phospholipase A, crotapotin and their combination
  • E. Habermann
  • P. Walsch
  • H. Breithaupt
Article

Summary

In order to obtain better insight into the potentiation of the toxicity of phospholipase A by crotapotin, we studied the distribution and elimination of these substances and of their combination.

Blood Plasma Concentration. Iodine-labelled phospholipase A leaves the bloodstream of mice and rabbits very quickly after i.v. application. Simultaneous injection of crotapotin speeds the elimination of the enzyme.

After subcutaneous application in mice the plasma concentration of phospholipase A depends on the quantity of enzyme injected. It is higher when the enzyme is complexed with crotapotin before injection. The plasma concentration of phospholipase A fails, however, to be proportional to the toxicity of the complex after subcutaneous application.

Crotapotin leaves the blood of mice also very quickly after i.v. application.

Organ Distribution. After i.v. application in mice, phospholipase A is heavily enriched in the liver. By simultaneous application of crotapotin, the enzyme is partially diverted to the kidneys. Only a small percentage of injected enzyme is found in the brain. This percentage is just significantly raised by simultaneous application of crotapotin. The diaphragm contains about the twofold amount of phospholipase A per wet weight as compared with other samples of skeletal musculature. With crotapotin, there is a slight increase of the radioactivity in all muscles investigated, with different degrees of significance.

Crotapotin is enriched in mouse kidneys after i.v. application.

Renal Elimination. The renal elimination of the acidic crotapotin is higher than that of the basic phospholipase A. In this respect, the latter resembles the basic polypeptide Trasylol®.

Doses of phospholipase A above 0.25 mg/kg cause intravital hemolysis. The hemolysis is prevented if a small amount of crotapotin is applied simultaneously.

Our findings show that the combination with crotapotin distinctly alters the pharmacokinetic behaviour of Crotalus terrificus phospholipase A. However, our data do not explain the tremendous increase of phospholipase A toxicity caused by the non-toxic crotapotin.

Key words

Snake Venom Phospholipase A Potentiation Iodine Labelling Pharmacokinetics 

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References

  1. Arndts, D.: Radioimmunologische Ultramikrobestimmungen von Proteinen und Polypeptiden: Entwicklung, Vergleich und Anwendungsmöglichkeiten. Inaug.-Dissertation, Gießen 1968.Google Scholar
  2. —, Räker, K. O., Török, P., Habermann, E.: Studien zur Verteilung und Elimination eines Proteinasen-Inhibitors mit Isotopentechniken. Arzneimittel-Forsch. (Drug Res.) 20, 667–674 (1970).Google Scholar
  3. Brazil, O. V.: Pharmacology of crystalline crotoxin. II. Neuromuscular blocking action. Mem. Inst. Butantan 33, 973–980 (1966).Google Scholar
  4. —, Excell, B. J.: Action of crotoxin and crotactin from the venom of Crotalus durissus terrificus (South american rattlesnake) on the frog neuromuscular function. J. Physiol. (Lond.) 212, 34–35 (1971).Google Scholar
  5. Breithaupt, H., Rübsamen, K., Walsch, P., Habermann, E.: In vitro and in vivo interactions between phospholipase A and a novel potentiator isolated from socalled crotoxin. Naunyn-Schmiedebergs Arch. Pharmak. 269, 403 (1971).Google Scholar
  6. Cheymol, J., Bourillet, F., Roch-Arveiller, M., Toan, T.: Effects neuromusculaires des venins des deux variétés de crotalus durissus terrificus. Arch. int. Pharmacodyn. 179, 40–55 (1969).Google Scholar
  7. Greenwood, F. C., Hunter, W. M., Glover, J. S.: The preparation of 131I-labelled human growth hormone of high specific radioactivity. Biochem. J. 89, 114–123 (1963).Google Scholar
  8. Habermann, E.: Gewinnung und Eigenschaften von Crotactin, Phospholipase A, Crotamin und “Toxin III” aus dem Gift der brasilianischen Klapperschlange. Biochem. Z. 329, 405–415 (1957).Google Scholar
  9. —: Pharmakokinetische Besonderheiten des Tetanus-Toxins und ihre Beziehungen zur Pathogenese des lokalen bzw. generalisierten Tetanus. Naunyn-Schmiedebergs Arch. Pharmak. 267, 1–19 (1970).Google Scholar
  10. —, Krusche, B.: Wirkung der Phospholipasen A und C auf Plasmalipoide und Erythrozyten in vivo. Biochem. Pharmacol. 11, 400–401 (1962).Google Scholar
  11. —, Neumann, W.: Die Hemmung der Hitzekoagulation von Eigelb durch Bienengift — ein Phospholipase-Effekt. Hoppe-Seylers Z. physiol. Chem. 297, 179–193 (1954).Google Scholar
  12. —, Räker, K. O., Zeuner, G.: Solid-phase-Radioimmunassay und Blutspiegel von Staphylokokken-α-Toxin. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 262, 165–182 (1969).Google Scholar
  13. —, Rübsamen, K.: Biochemical and pharmacological analysis of the so-called crotoxin. In: de Vries-Kochva, ed.: Toxins of animal and plant origin. Vol. 1: Proceedings of the Second International Symposium on Animal and Plant Toxins, Tel Aviv 1970. pp. 333–341. London: Gordon and Breach 1971.Google Scholar
  14. Hagemann, E., Schmidt, G.: Ratte und Maus — Versuchstiere in der Forschung, p. 240. Berlin: Verlag W. de Gruyter & Co. 1960.Google Scholar
  15. Hendon, R. A., Fraenkel-Conrat, H. L.: Biological roles of the two components of crotoxin. Proc. nat. Acad. Sci. (Wash.) 68, 1560–1563 (1971).Google Scholar
  16. McConahey, P. J., Dixon, F. J.: A method of trace iodination of proteins for immunologic studies. Int. Arch. Allergy 29, 185–189 (1966).Google Scholar
  17. Neumann, W. P., Habermann, E.: Über Crotactin, das Haupttoxin des Giftes der brasilianischen Klapperschlange (Crotalus terrificus terrificus). Biochem. Z. 327, 170–185 (1955).Google Scholar
  18. Parnas, I., Russell, F. E.: In Animal toxins, pp. 401–415. F. E. Russell and P. R. Saunders, eds. Oxford-New York: Pergamon 1967.Google Scholar
  19. Robbins, J. B., Haimovich, J., Sela, M.: Purification of antibodies with immunoadsorbents prepared using bromacetyl cellulose. Immunochemistry 4, 11–22 (1967).Google Scholar
  20. Rübsamen, K., Breithaupt, H., Habermann, E.: Biochemistry and pharmacology of the crotoxin complex. I. Subfractionation and recombination of the crotoxin complex. Naunyn-Schmiedebergs Arch. Pharmak. 270, 274–288 (1971).Google Scholar
  21. Russell, F. E.: Comparative pharmacology of some animal toxins. Fed. Proc. 26, 1206 (1967).Google Scholar
  22. Sabato, G. di: The role of the tyrosyl groups on the mechanism of action of chicken heart lactic dehydrogenase. Biochemistry 4, 2288–2296 (1965).Google Scholar
  23. Slotta, K. H., Fraenkel-Conrat, H. L.: Schlangengifte, III. Mitteilung: Reinigung und Krystallisation des Klapperschlangengiftes. Ber. dtsch. chem. Ges. 71, 1076–1081 (1938).Google Scholar

Copyright information

© Springer-Verlag 1972

Authors and Affiliations

  • E. Habermann
    • 1
  • P. Walsch
    • 1
  • H. Breithaupt
    • 1
  1. 1.Pharmakologisches Institut der Universität GießenGießenGermany

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