Significance of Induction Phenomena

  • K. J. Netter
  • R. Kahl
  • C. R. Elcombe
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 1)


A number of foreign compounds induce the proliferation of the hepatic smooth endoplasmatic reticulum and thereby increase the activity of monooxygenases that metabolize drugs and other foreign compound. With reference to the safety of food additives some antioxidants have been examined by various authors for their inducing capacity, in doses well above those ingested with treated food and above the stipulated accepted daily intake (ADI). Thus feeding of rats with the very high dose of 500 mg/kg body weight of butylated hydroxtoluene (BHT) resulted in an increase in its own oxidative metabolism. Also in monkeys BHT produces an inductive increase of microsomal enzyme activity, cytochrome P 450, and a proliferation of smooth endoplasmatic reticulum. The closely related antioxidant butylated hydroxyanisole (BHA) leads to similar effects in mice. Recent studies with ethoxyquin (EQ) have shown that this antioxidant stimulates the formation of a form of cytochrome P 450 which resembles the phenobarbital-inducible type. EQ itself is also an inhibitor of mixed function monooxygenase. The naturally occuring flavouring agents safrole and isosafrole in high doses also induce hepatic mono-oxygenations. Spectroscopic examination has revealed, however, that another type of cytochrome with characteristic binding of a suspected safrole metabolite is produced. This complex shows absorption maxima at 427 and 455nm and can be dissociated by adding a number of different lipophilic agents, including safrole itself. In a time dependent displacement reaction the characteristic spectrum decreases and is replaced by a classical binding spectrum of the displacer itself.

By these examples it can be shown that food additives exert a number of effects on hepatic drug inactivating systems. However, no risk of hepatic changes can be seen from the small amounts of antioxidants ingested in balanced human nutrition.


Food Additive Liver Weight Butylate Hydroxy Toluene Microsomal Protein Styrene Oxide 
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  1. Adamson, I.Y.R., Bowden, D.H., Cote, M.G., Witschi, H.: Laboratory Investigation 36, 26 (1977)PubMedGoogle Scholar
  2. Astill, B.D., Mills, J., Fassett, D.W., Roudabush, R.L., Terhaar, C.J.: Agricultural and Food Chemistry 10, 315 (1962)CrossRefGoogle Scholar
  3. Bridges, J.W., Dickins, M., Moloney, S.J., Elcombe, C.R., Netter, K.J.: Biochemical Pharmacology, in press (1977)Google Scholar
  4. Commission of the European Communities: Ethoxyquin Working Document 1295/VI/ 74-E (1974)Google Scholar
  5. Elcombe, C.R., Bridges, J.W., Gray, T.J.B., Nimmo-Smith, R.H., Netter, K.J.: Biochemical Pharmacology 24, 1427 (1975)CrossRefGoogle Scholar
  6. Epstein, S.S., Fujii, K., Andrea, J., Mantel, N.: Toxicology and applied Pharmacology 16, 321 (1970)PubMedCrossRefGoogle Scholar
  7. Estabrook, R.W., Hildebrandt, A.G., Baron, J., Netter, K.J., Leibman, K.C.: Biochemical biophysical Research Communications 42, 132 (1971)CrossRefGoogle Scholar
  8. Gilbert, D., Golberg, L.: Food and Cosmetics Toxicology 3, 417 (1965)PubMedCrossRefGoogle Scholar
  9. Gilbert, D., Golberg, L.: Food and Cosmetics Toxicology 5, 481 (1967)PubMedCrossRefGoogle Scholar
  10. Kahl, R., Netter, K.J.: Toxicology and applied Pharmacology, 40, 473 (1977)PubMedCrossRefGoogle Scholar
  11. Lindner, E.: Toxikologie der Nahrungsmittel, p. 53. Stuttgart: Georg Thieme Verlag (1974)Google Scholar
  12. Long, E.L., Nelson, A.A., Fitzhugh, O.G., Hansen, W.H.: Archives of Pathology 75, 595 (1963)Google Scholar
  13. Marino, A.A., Mitchell, J.T.: Proceedings of the Society of experimental Biology and Medicine 140, 122 (1972)Google Scholar
  14. Parke, D.V., Rahman, H.: Biochemical Journal 119, 53 p (1970)Google Scholar
  15. Parke, D.V.: Biochemical Journal 130, 53 p (1972)Google Scholar
  16. Parke, D.V., Rahim, A., Walker, R.: Biochemical Pharmacology 23, 1871 (1974)PubMedCrossRefGoogle Scholar
  17. Ryan, D., Lu, A.Y.H., Kawalek, J., West, S.B., Levin, W.: Biochemical and biophysical Research Communications 64, 1134 (1975)PubMedCrossRefGoogle Scholar
  18. Saheb, W., Witschi, H.: Toxicology and applied Pharmacology 33, 309 (1975)PubMedCrossRefGoogle Scholar
  19. Schulte Hermann, R., Koransky, W., Leberl, C., Noack, G.: Virchows Archiv, Abt. B, Zellpathologie 9, 125 (1971)Google Scholar
  20. Speier, J.L., Wattenberg, L.W.: Journal of the National Cancer Institute 55, 469 (1975)PubMedGoogle Scholar
  21. Stuckey, B.N.: In: (Th. E. Furia, ed.), Handbook of Food Additives 2nd ed. p. 215 Cleveland: CRC Press (1975)Google Scholar
  22. Tyndall, R.L., Colyer, S., Clapp. N.: International Journal of Cancer 16, 184 (1975)CrossRefGoogle Scholar
  23. WHO Food Additives Series No. 5: Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents, p. 148, World Health Organization, Geneva (1974)Google Scholar
  24. WHO Technical Report Series No. 599: Evaluation of certain food additives. Annex 2, p. 28, World Health Organization, Geneva (1976)Google Scholar
  25. Wiebel, F.J., Leutz, J.C., Diamond, L., Gelboin, H.V.: Archives of Biochemistry and Biophysics 144, 78 (1971)PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • K. J. Netter
    • 1
  • R. Kahl
    • 2
  • C. R. Elcombe
    • 3
  1. 1.Institut für Pharmakologie und ToxikologieUniversität MarburgMarburg/ LahnGermany
  2. 2.Pharmakologisches Institut der Universität MainzMainzGermany
  3. 3.Department of PharmacologyMedical College of WisconsinMilwaukeeUSA

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