Journal of Cancer Research and Clinical Oncology

, Volume 109, Issue 1, pp 16–22 | Cite as

Influence of a prolonged treatment with disulfiram andd-penicillamine on nitrosodiethylamine-induced biological and biochemical effects

II. Investigations on trace elements in the liver
  • J. Schuhmacher
  • H. R. Scherf
  • B. Bertram
  • E. Frei
  • H. Hauser
  • M. Wiessler
Original Papers Experimental Oncology

Summary

The influence of a 28-week treatment with disulfiram (DSF),d-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%–80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.

Key words

Nitrosodiethylamine Liver tumors Disulfiram d-penicillamine Trace elements Rats 

Abbreviations

DSF
disulfiram
DDTC
diethyldithiocarbamic acid
PA
d-ββ dimethylcystein,d-penicillamine
NDEA
nitrosodiethylamine

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References

  1. Bertram B, Schuhmacher J, Frei E, Frank N, Wiessler M (1982) Effects of disulfiram on mixed function oxidase system and trace element concentration in the liver of rats. Biochem Pharmacol 31:3613–3619PubMedGoogle Scholar
  2. Brown DA, Chatel KW, Chan AY, Knight B (1980) Cytosolic levels and distribution of calcium, copper, and zinc in pretumorous livers from diethylnitrosamine-exposed mice and in non-cancerous kidneys from cancer patients. Chem Biol Interact 32:13–27PubMedGoogle Scholar
  3. Burch RE, Williams RV, Hahn HK, Nayak RV, Sullivan JF (1974) Trace element content and enzymatic activities in tisues of zinc deficient pigs. In: Hoeckstra WG, Suttie JW, Ganther HE, Mertz W (eds) Trace element metabolism in animals 2. University Park Press, Baltimore, pp 513–515Google Scholar
  4. Chapvil M, Ryan JN, Zukoski CF (1972) Effects of zinc on lipid peroxidation in liver microsomes and mitochondrial. Proc Soc Exp Biol Med 141:150–153PubMedGoogle Scholar
  5. De Alvare LR, Goda K, Kimura T (1976) Mechanism of superoxide anion scavening reaction by bis-(salicylato)-copper II complex. Biochem Biophys Res Commun 69:687–694PubMedGoogle Scholar
  6. Duncan JR, Hurley LS (1978) Thymidine kinase and DNA polymerase activity in normal and zinc deficient developing rat embryos. Proc Soc Exp Biol Med 159:39–43PubMedGoogle Scholar
  7. Faiman MD, Dodd DE, Hanzlik RE (1978) Distribution of S35-disulfiram and metabolites in mice and metabolism of S35-disulfiram in the dog. Res Commun Chem Pathol Pharmacol 21:543–567PubMedGoogle Scholar
  8. Fare G (1966) The effect of cupric oxyacetate on rat liver damage associated with five poisons of related chemical structure. Br J Cancer 20:569–581PubMedGoogle Scholar
  9. Fiala S, Trout LC, Ostrander H, Fiala AE (1980) γ-glutamyltransferase and the inhibition of azo dye-produced neoplasia by concomitant administration of disulfiram. J Natl Cancer Inst 64:267PubMedGoogle Scholar
  10. Frank N, Hadjiolov D, Bertram B, Wiessler M (1980) Effect of disulfiram on the alkylation of rat liver DNA by nitrosodiethylamine. J Cancer Res Clin Oncol 97:209–212PubMedGoogle Scholar
  11. Friedman S, Kaufmann D (1965) 3,4 Dihydroxyphenylethylamine β-hydroxylase. Physical properties, copper content and role of copper in the catalytic activity. J Biol Chem 240:4763–4773PubMedGoogle Scholar
  12. Gawthorne JM, Howell JMcC, Wyburn RS (1981) Effects of thiomolybdate in rats fed a high copper diet. In: Gawthorne JM, Howell JMcC, White CL (eds) Trace element metabolism in man and animals. Springer, Berlin Heidelberg New York, pp 553–555Google Scholar
  13. Hadjiolov D, Frank N, Schmähl D (1977) Inhibition of diethylnitrosamine-induced strand breaks in liver DNA by disulfiram. Z Krebsforsch 90:107–109Google Scholar
  14. Howell JS (1958) The effect of copper acetate on p-dimethylaminoazobenzene carcinogenesis in the rat. Br J Cancer 12:594–611PubMedGoogle Scholar
  15. Irving CC, Tice AJ, Murphy WM (1979) Inhibition of N-n-butyl-N-(4-hydroxybutyl)nitrosamine induced urinary bladder cancer in rats by administration of disulfiram in the diet. Cancer Res 39:3040–3043PubMedGoogle Scholar
  16. Kharasch N (1979) Trace metals in health and diseases. Raven, New YorkGoogle Scholar
  17. Lengfelder E (1979) On the action of diethyldithiocarbamate as inhibitor of copper-zinc superoxide dismutase. Z Naturforsch 34c:1292–1294Google Scholar
  18. Leuthauser SWC, Oberley LW, Oberley TD, Sorenson JRJ, Ramakrishna K (1981) Anti-tumor effect of a copper coordination compound with superoxide dismutase-like activity. J Natl Cancer Inst 66:1077–1081PubMedGoogle Scholar
  19. Malejka-Giganti D, McIver RC, Rydell RE (1980) Inhibitory effect of disulfiram on mammary tumor induction by N-2-fluorenylacetamide and on its metabolic conversion to N-hydroxy N-2-fluorenylacetamide. J Natl Cancer Inst 64:1471–1477PubMedGoogle Scholar
  20. Mills CF, Brenner J, Young BW, Davies NT (1981) Effects of thioanions of molybdenum and tungsten upon copper metabolism. In: Gawthorne JM, Howell JMcC, White CL (eds) Trace element metabolism in man and animals. Springer, Berlin Heidelberg New York, pp 549–551Google Scholar
  21. Neal RA (1980) Microsomal enzymes and the toxicity of thiono-sulfur compounds. In: Coon MJ, Conney AH, Estabrook RW, Gelboin HV, Gilette JR, O'Brien PJ (eds) Microsomes drug oxidations and chemical carcinogenesis. Academic, New York, pp 791–798Google Scholar
  22. Oberley LW, Buettner GR (1979) The role of superoxide dismutase in cancer: A review. Cancer Res 39:1141–1149PubMedGoogle Scholar
  23. Oskarson A, Tjälve H (1980) Effects of diethyldithiocarbamate and penicillamine on the tissue distribution of63-NiCl2 in mice. Arch Toxicol 45:45–52PubMedGoogle Scholar
  24. Petering DH, Petering HG (1975) Metal chelates of 3-ethoxy-2-oxobutyraldehyde bis (thiosemicarbazone)-H2KTS. In: Eichler E, Farah A, Herken H, Welch AD (eds) Handbook of experimental pharmacology, vol 38/2. Springer, Heidelberg New York, pp 841–849Google Scholar
  25. Prasad AS (1976) Trace elements in human health and disease, vol I. Zinc and copper. Academic, New YorkGoogle Scholar
  26. Prasad AS (1982) Current topics in nutrition and disease, vol 6. Clinical biochemical and nutritional aspects of trace elements. Liss, New YorkGoogle Scholar
  27. Sakai K, Murata N, Chiba K, Yamane Y (1981) Effect of copper administration on the incorporation of3H-thymidine into the liver DNA of rats stimulated by dimethylnitrosamine and diethylnitrosamine. Carcinogenesis 2:1261–1266PubMedGoogle Scholar
  28. Schmähl D, Krüger FW, Habs M, Diehl B (1976) Influence of disulfiram on the organotropy of the carcinogenic effect of dimethylnitrosamine and diethylnitrosamine in rats. Z Krebsforsch 85:271–276Google Scholar
  29. Schuhmacher J, Maier-Borst W, Hauser H (1977) A half automated, non-time consuming radiochemical separation scheme for determination of 25 trace elements and biological specimen. J Radioanal Chem 37:503–509Google Scholar
  30. Schweinsberg F, Bürkle V (1981) Wirkung von Disulfiram auf die Toxizität und Carcinogenität von N-Methyl N-Nitrosobenzylamin bei Ratten. J Cancer Res Clin Oncol 102:43–47PubMedGoogle Scholar
  31. Smith LE (1962) Cobalt. In: Comar CL, Bronner F (eds) Mineral metabolism, vol II. Academic, New York, part B, pp 349–369Google Scholar
  32. Starý J (1964) The solvent extraction of metal chelates. Pergamon, OxfordGoogle Scholar
  33. Sternlieb J (1980) Copper and the liver. Gastroenterology 78:1615–1628PubMedGoogle Scholar
  34. Strömme H (1964a) Interactions of disulfiram and diethyldithiocarbamate with serum proteins studied by means of a gel-filtration technique. Biochem Pharmacol 14:381–391Google Scholar
  35. Strömme H (1964b) 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 14:393–410Google Scholar
  36. Tobey RA, Enger MD, Griffith JK, Hildebrand CE (1982) Zinc induced resistance to alkylating agents: Lack of correlation between cell survival and metallothionein content. Toxicol Appl Pharmacol 64:72–78PubMedGoogle Scholar
  37. Törrönen R, Alakuijala P, Marselos M (1977) Chelating agents and hepatic drug metabolism in the rat. Arch Int Pharmacodyn Ther 226:11–20PubMedGoogle Scholar
  38. Underwood EJ (1971) Trace elements in human and animal nutrion, 3rd ed. Academic, LondonGoogle Scholar
  39. Wattenberg LW (1975) Inhibition of diemethylhydrazine-induced neoplasia of the large intestine by disulfiram. J Natl Cancer Inst 54:1005–1006PubMedGoogle Scholar
  40. Wattenberg LW (1978) Inhibition of chemical carcinogenesis. J Natl Cancer Inst 60:11–18PubMedGoogle Scholar
  41. Wesch H, Jonak R, Nemetschek-Gansler H, Riedl H, Nemetschek T (1978) Der Einfluß von d-Penicillamin auf den Gehalt einiger Organe an Spurenelementen sowie auf die mechanischen Eigenschaften von Kollagen. Z Naturforsch 33c:346–358Google Scholar
  42. Yamane Y, Sakai K (1973) Suppressive effect of concurrent administration of metal salts on carcinogenesis by 3′methyl-4-(dimethylamino)azobenzene and the effect of these metals on aminoazo dye metabolism during carcinogenesis. Gan 64:563–573PubMedGoogle Scholar
  43. Yamane Y, Sakai K (1980) Effects of metals on chemical carcinogenesis. Proceedings 6th Symposium Environmental Pollutants and Toxicology, Nagasaki, Oct 1979. J Pharmacobiodyn 3:19Google Scholar
  44. Yamane Y, Sakai K, Kojima S (1976) Mechanism of suppressive effect of basic cupric acetate on rat liver carcinogenesis by ethionine. Gan 67:295–302PubMedGoogle Scholar
  45. Yamane Y, Sakai K, Shibata M, Chiba K (1977) Suppressive effect of copper on ethylation of rat liver DNA with ethionine in vivo. Gan 68:713PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • J. Schuhmacher
    • 1
  • H. R. Scherf
    • 2
  • B. Bertram
    • 2
  • E. Frei
    • 2
  • H. Hauser
    • 1
  • M. Wiessler
    • 2
  1. 1.German Cancer Research CenterInstitute of Nuclear MedicineHeidelbergFederal Republic of Germany
  2. 2.German Cancer Research CenterInstitute of Toxicology and ChemotherapyHeidelbergFederal Republic of Germany

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