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Studies of The Mechanism of Action of Hepatotoxicity of 2,3,7,8- Tetrachlorodibenzo-P-Dioxin (TCDD) and Related Compounds

  • G. D. Sweeney
  • K. G. Jones
Part of the Environmental Science Research book series (ESRH, volume 26)

Abstract

TCDD causes liver damage, porphyria, chloracne, thymic atrophy and damage to other organs in rats and mice. The porphyria due to TCDD reflects interference with an enzyme, uroporphyrinogen decarboxylase, converting uroporphyrinogen to coproporphyrinogen. We studied TCDD liver toxicity in an inbred strain of mice using histological criteria and porphyria as indices of severity. Toxicity of TCDD was enhanced in C57B1/6J (responsive) mice in comparison with DBA/2J (non-responsive) mice. This difference is attributed to the high affinity binding site in hepatic cytosol of C57 mice. Interaction with this site is required for induction of aryl hydrocarbon hydroxylase (AHH) and other coordinately expressed functions under control of a regulatory gene (‘Ah’) which differs in C57 and DBA mice. We compared the effects of TCDD in C57/B1 mice depleted of iron by venesection with control animals not deficient in iron. Low iron animals were protected against porphyria and liver damage but not against thymic atrophy or chloracne. Dependence upon the Ah gene and on non-heme tissue iron has suggested a free radical mechanism initiating lipid peroxidation. The finding that dietary supplements of butylated hyroxy anisole also protect against histological changes in the liver and porphyria is consistent with this hypothesis.

Keywords

Porphyria Cutanea Tarda High Affinity Binding Site Tissue Iron Thymic Atrophy Aryl Hydrocarbon Hydroxylase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bleiberg, J., Wallen, M., Brodkin, R., and Applebaum, I.L. Industrially acquired porphyria. Arch Dermatol 89: 793 - 797, 1964.CrossRefGoogle Scholar
  2. Elder, G.H. Porphyrin metabolism in porphyria cutanea tarda. Seminars in Hematol, 14: 227–242, 1977.MathSciNetGoogle Scholar
  3. Goldstein, J.A., Hickman, P., Bergman, H., and Vos, J.G. Hepatic porphyria induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in the mouse. Res Commun in Chem Pathol & Pharmacol, 6: 919–928, 1973.Google Scholar
  4. Goldstein, J.A., Hickman, P. and Bergman, H. A comparative study of two polychlorinated biphenyl mixtures (Aroclors 1242 and 1016) containing 42% chlorine on induction of hepatic porphyria and drug metabolizing enzymes. Toxicol & Appl Pharmacol, 32:461- 473, 1975.CrossRefGoogle Scholar
  5. Goldstein, J.A., Hickman, P. and Bergman, H. Induction of hepaticporphyria and drug-metabolizing enzymes by 2,3,7,8-tetrachlorodi- benzo-p-dioxin (TCDD). Fed Proc 35: 708, 1976.Google Scholar
  6. Jirasek, L., Kalensky, J., Kubec, K., Pazderova, J., and Lukas, E. Acne chlorina porphyria cutanea tarda and other manifestations of general intoxication during the manufacture of herbicides. II. Cesk Dermatol, 49: 145–147, 1974.Google Scholar
  7. Jones, G., and Butler, W.H. A morphological study of the liver lesion induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. J Pathol, 112: 93–97, 1974.CrossRefGoogle Scholar
  8. Jones, G., and Greig, J.B. Pathological changes in the liver of mice given 2,3,7,8-tetrachlorodibenzo-p-dioxin. Experientia, 31: 1315–1317, 1975.CrossRefGoogle Scholar
  9. Jones, K.G., and Sweeney, G.D. Quantitation of urinary porphyrins by use of second-derivative spectroscopy. Clin Chem, 25: 71–74, 1979.Google Scholar
  10. Jones, K.G., and Sweeney, G.D. Dependence of the porphyrinogenic effect of 2,3,7,8 tetrachlorodibenzo(p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness. Toxicol & Appl Pharmacol, 53: 42–49, 1980.CrossRefGoogle Scholar
  11. Jones, K.G., and Sweeney, G.D. Dependence of the porphyrinogenic effect of 2,3,7,8 tetrachlorodibenzo(p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness. Toxicol & Appl Pharmacol, 53: 42–49, 1980.CrossRefGoogle Scholar
  12. May, G. Chloracne from the accidental production of tetrachlorodi- benzodioxin. Brit J Industr Med, 30: 276–283, 1973.Google Scholar
  13. Poland, A., and Kende, A. 2,3,7,8-tetrachlorodibenzo-p-dioxin:environmental contaminant and molecular probe. Fed Proc, 35: 2404–2411, 1976.Google Scholar
  14. Poland, A., Glover, E., and Kende, A.S. Stereospecific, high affiniity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem, 251: 4936–4946, 1976.Google Scholar
  15. Robinson, J.R., Considine, N., and Nebert, D.W. Genetic expression of aryl hydrocarbon hydroxylase induction. Evidence for the involvement of other genetic loci. J Bio Chem, 249: 5851–5859, 1974.Google Scholar
  16. Strik, J.J.T.W.A., Doss, M., Schraa, G., Robertson, L.W., von Tiepermann, R., and Harmsen, E.G.M. Coproporphyrinuria and chronic hepatic porphyria type A found in farm families from Michigan (U.S.A.) exposed to polybrominated biphenyls (PBB). In: Strik, J.J.T.W.A. and Koeman, J.H., eds. Chemical Porphyria in Man. Elsevier/North Holland Biomedical Press, pp. 29–53, 1979.Google Scholar
  17. Sweeney, G.D. and Jones, K.G. Porphyria cutanea tarda: clinical and laboratory studies. Can Med Assoc J, 120: 803–807, 1979.Google Scholar
  18. Sweeney, G.D., Jones, K.G., Cole, F.M., Basford, D., and Krestynski, F. Iron deficiency prevents liver toxicity of 2,3,7,8-tetra- chlorodibenzo(p)-dioxin (TCDD). Science 204: 332–335, 1979.CrossRefADSGoogle Scholar
  19. Urabe, H., Koda, H., and Asahi, M. Present state of Yusho patients. Annals N Y Acad Sci, 320: 273–276, 1979.ADSGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • G. D. Sweeney
    • 1
  • K. G. Jones
    • 1
  1. 1.McMaster UniversityHamiltonCanada

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