Advertisement

Archives of Toxicology

, Volume 41, Issue 1, pp 79–88 | Cite as

The antihepatotoxic activity of dithiocarb as compared with six other thio compounds in mice

  • C. -P. Siegers
  • O. Strubelt
  • M. Völpel
Article

Abstract

In mice, diethyldithiocarbamate (dithiocarb, 100 mg/kg i.p.) completely prevented the increments of serum enzyme activities (GOT, GPT, SDH) induced by oral administration of carbon tetrachloride (0.1 ml/kg), allyl alcohol (0.05 ml/kg), bromobenzene (0.25 ml/kg), and thioacetamide (50 mg/kg). In this respect, cysteine (200 mg/kg i.p.) was active against CCl4 and bromobenzene, cysteamine (100 mg/kg i.p.) against CCl4 and allyl alcohol, penicillamine (100 mg/kg i.p.) against allyl alcohol, thiazolidine carbonic acid (100 mg/kg i.p.) against bromobenzene, and thioctic acid (100 mg/kg i.p.) against allyl alcohol and thioacetamide. Dimercaprol (100 mg/kg i.p.) had a weak antidotal effect only against allyl alcohol poisoning. None of the tested antidotes inhibited serum enzyme elevations evoked by dimethyl nitrosamine (100 mg/kg p.o.). These findings prove the antihepatotoxic activity of diethyldithiocarbamate to be superior to that of all other thio compounds under observation.

The lowest dose of dithiocarb active against carbon tetrachloride was 25 mg/kg i.p. The dose-response curves for serum-enzyme elevations induced by carbon tetrachloride (0.1–4 ml/kg p.o.) were shifted to the right under the influence of dithiocarb indicating a competitive antagonism. Dithiocarb (100 mg/kg i.p.) depressed the p-hydroxylation of aniline in the 9000 x g liver homogenate supernatant of mice by about 55%. Thus, the antihepatotoxic activity of dithiocarb seems to be the consequence of a decreased oxidase activity.

Key words

Diethyldithiocarbamate Cysteine Cysteamine d-Penicillamine Dimercaprol Thiazolidine carbonic acid Thioctic acid Carbontetrachloride Allyl alcohol Bromobenzene Thioacetamide Dimethylnitrosamine Hepatitis, toxic Aminotransferases Mixed function oxidases 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ammon, R., Berninger, H., Haas, H. J., Landsberg, I.: Thioacetamid-Sulfoxid, ein Stoffwechselprodukt des Thioacetamids. Arzneimittel-Forsch. 17, 521–523 (1967)Google Scholar
  2. Bini, A., Vecchi, G., Vivoli, G., Vannini, V., Cessi, C.:Detection of early metabolites in rat liver after administration of CCl4 and CBrCl3. Pharmacol. Res. Commun. 7, 143–149 (1975)Google Scholar
  3. Eger, W.: Über Cystein, Homocystein, Cystathionin und Cysteamin als nekrotrope Leberschutzstoffe in Verbindung mit Traubenzucker und Fruchtzucker. Medizinische 17, 618–623 (1957)Google Scholar
  4. Fowler, J. S. L.: Carbon tetrachloride metabolism in the rabbit. Brit. J. Pharmacol. 37, 733–737 (1969)Google Scholar
  5. Frimmer, M., Waldvogel, A., Weil, G.: Schutzwirkung von Thioctsäure gegen die Kalium-freisetzende Wirkung des Phalloidins an der isoliert perfundierten Rattenleber. Klin. Wschr. 46, 1281–1289 (1968)Google Scholar
  6. Frimmer, M., Petzinger, E., Homann, J.: Phalloidinantagonisten. 4. Mitteilung: Thioctsäure, SH-Verbindungen, Rifampicin, Choleretika, Dexamethason, Östradiol, unspezifische Hemmstoffe und unwirksame Verbindungen. Arzneimittel-Forsch. 25, 1881–1884 (1975)Google Scholar
  7. Gutbrod, H., Kornberger, E. J., Stille, G., Wolf, V.: Eigenschaften einer neuen antinekrotischen Kombination für die Behandlung akuter Leberschäden. Acta hepat. (Hamburg) 5, 1–12 (1957)Google Scholar
  8. Homburg, Chemiewerk; Thioctacid (Thioctsäure Homburg). Frankfurt 1975Google Scholar
  9. Hunter, A. L., Neal, R. A.: Inhibition of hepatic mixed-function oxidase activity in vitro and in vivo by various thionosulfur-containing compounds. Biochem. Pharmacol. 24, 2199–2205 (1975)Google Scholar
  10. Janovics, T., Tako, J.: Die Anwendung von 2,3-Dimercaptopropanol (BAL) bei diffusen Leberparenchymschädigungen. Schweiz. med. Wschr. 80, 933–936 (1950)Google Scholar
  11. Jollow, D. J., Mitchell, J. R., Zampaglione, N., Gillette, J. R.: Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenze oxide as the hepatotoxic metabolite. Pharmacology (Basel) 11, 151–169 (1974)Google Scholar
  12. Kirnberger, E. J., Braun, W., Stille, G., Wolf, V.: Beziehungen zwischen Leberschutz und Zuckerstoffwechsel. Arzneimittel-Forsch. 8, 72–76 (1958)Google Scholar
  13. Lange, P., Jung, F.: Die Verringerung der Lebertoxizität von Tetrachlorkohlenstoff durch Diäthyldithiocarbamat und 3-(o-Tolyl)-4-(nitro)-sydnon. Acta biol. med. germ. 27, 425–434 (1971)Google Scholar
  14. Lange, J., Schumacher, K., Witscher, H. P.: Die Behandlung der chronisch-aggressiven Hepatitis mit d-Penicillamin. Dtsch. med. Wschr. 96, 139–145 (1971)Google Scholar
  15. Legros, J.: Paracetamol and the liver. Animal studies — a theoretical basis for treatment. J. int. Med. Res. 4, (Suppl. 4), 46–54 (1976)Google Scholar
  16. Lieber, C. S., Rubin, E., De Carli, L. M.: Hepatic microsomal ethanol oxidizing system (MEOS): differentiation from alcohol dehydrogenase and NADPH oxidase. Biochem. biophys. Res. Commun. 40, 858–865 (1970)Google Scholar
  17. Lutz, L. M., Glende, E. A., Recknagel, R. O.: Protection by diethyldithiocarbamate against carbon tetrachloride lethality in rats and against carbon tetrachloride-induced lipid peroxidation in vitro. Biochem. Pharmacol. 22, 1729–1734 (1973)Google Scholar
  18. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B.: Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. exp. Ther. 187, 185–194 (1973)Google Scholar
  19. Rees, K. R., Tarlow, M. J.: The hepatotoxic action of allyl formate. Biochem. J. 104, 757–761 (1967)Google Scholar
  20. Reid, W. D., Christie, B., Eichelbaum, M., Krishna, G.: 3-methyl-cholanthrene blocks hepatic necrosis induced by administration of bromobenzene or carbon tetrachloride. Exp. molec. Path. 15, 363–372 (1971)Google Scholar
  21. Reynolds, E. S., Moslen, M. T.: Chemical modulation of early carbon tetrachloride liver injury. Toxicol. appl. Pharmacol. 29, 377–388 (1974)Google Scholar
  22. Sakaguchi, T., Nishimura, H., Masuda, K., Tsuge, I., Onishi, K., Tatsumi, H.: The relationship between chemical structure and protective effect of dithiocarbamate derivates against experimental hepatic injury induced by carbon tetrachloride administration in rats. Biochem. Pharmacol. 15, 756–758 (1966)Google Scholar
  23. Schlicht, I.: Autoradiographische und radiochromatographische Untersuchungen der Verteilung und des Stoffwechsels von Thioacetamid. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 268, 310–322 (1971)Google Scholar
  24. Strömme, J. H.: Metabolism of disulfiram and diethyldithiocarbamate in rats with demonstration of an in vivo ethanol-induced inhibition of the glucuronic acid conjugation of the thiol. Biochem. Pharmacol. 14, 393–410 (1965)Google Scholar
  25. Strubelt, O., Siegers, C.-P., Schütt, Atsuko: The curative effects of cysteamine, cysteine and dithiocarb in experimental paracetamol poisoning. Arch. Toxicol. 33, 55–64 (1974)Google Scholar
  26. Sunderman, F. W.: Diethyldithiocarbamate therapy of thallotoxicosis. Amer. J. med. Sci. 253, 107–118 (1967)Google Scholar
  27. Sunderman, F. W., Sunderman, F. W., Jr.: Nickel poisoning. VIII. Dithiocarb: a new therapeutic agent for persons exposed to nickel carbonyl. Amer. J. med. Sci. 236, 26–31 (1958)Google Scholar
  28. Tonkelaar, E. M., van Loogten, M. J.: Protective action of dithiocarbamates on experimental liver damage produced by carbon tetrachloride. Toxicol. appl. Pharmacol. 30, 96–106 (1974)Google Scholar
  29. Varga, F., Mekes, J., Molnar, Z.: Die Leberschutzwirkung von Cystein, Homocysteinthiolacton und-N-Acetylhomocysteinthiolacton bei experimenteller Leberschädigung. Arzneimittel-Forsch. 13, 867–871 (1963)Google Scholar
  30. Wilson, J. T., Frohman, L. A.: Concomitant association between high plasma levels of growth hormone and low hepatic mixed-function oxidase activity in the young rat. J. Pharmacol. exp. Ther. 189, 255–270 (1974)Google Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • C. -P. Siegers
    • 1
  • O. Strubelt
    • 1
  • M. Völpel
    • 2
  1. 1.Abteilung für ToxikologieLübeckGermany
  2. 2.Abteilung für Pathologie der Medizinischen Hochschule LübeckLübeckGermany

Personalised recommendations