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Cytochrome P-450 in the Activation and Inactivation of Carcinogens

  • Helmut Greim
  • Peter Czygan
  • Anthony J. Garro
  • Ferenc Hutterer
  • Fenton Schaffner
  • Hans Popper
  • Otto Rosenthal
  • David Y. Cooper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 58)

Summary

The capacity of isolated mouse liver microsomes to alter the mutagenicity for bacteria of the primary carcinogen N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) and the secondary one dimethylni-trosamine (DMN) was studied. Microsomal activation of DMN and in-activation of MNNG were decreased by protein- and protein-choline-deficient diets and were increased by pretreatment with microsomal enzyme inducers. The decrease and increase paralleled the content of cytochrome P-450 present in the different microsomal preparations. With human liver microsomes of differing cytochrome P-450 contents similar correlation was obtained, whereas normal rat liver microsomes did not activate or inactivate DMN or MNNG. Oxidative de-methylation of DMN by mouse liver microsomes and the activation of DMN to a mutagen followed similar kinetics. Both reactions were inhibited by carbon monoxide and the inhibition was maximally reversed by monochromatic light at 450 nm. These observations indicate that at least some carcinogens are activated or inactivated by the unspecific cytochrome P-450 dependent enzyme system, suggesting that the extent of this biotransformation may be one factor influencing human carcinogenesis.

Keywords

Liver Microsome Human Liver Microsome Formaldehyde Formation Microsomal Preparation Hepatic Microsome 
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. Alvares, A. P., Bickers, D. R., and Kappas, A. 1973. Polychlor-inated biphenyls: A new type of inducer of cytochrome P-448 in the liver. Proc. Natl. Acad. Sci. USA 70:1321–1325.PubMedCrossRefGoogle Scholar
  2. Ames, B. N., Durston, W. E., Yamasaki, E., and Lee, F. D. 1973a. Carcinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl. Acad. Sci. USA 70:2281–2285.CrossRefGoogle Scholar
  3. Ames, B. N., Lee, F. D., and Durston, W. E. 1973b. An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc. Natl. Acad. Sci. USA 70:782–786.CrossRefGoogle Scholar
  4. Conney, A. H., Welch, R., Kuntzman, R., Poland, A., Poppers, P. J., Finster, M., Wolff, J. A., Munro-Faure, A. D., Peck, A. W., Bye, A., Chang, R., and Jacobson, M. 1971. Effects of environmental chemicals on the metabolism of drugs, carcinogens, and normal body constituents in man. Ann. N. Y. Acad. Sci. 179:155–172.PubMedCrossRefGoogle Scholar
  5. Czygan, P., Greim, H., Garro, A. J., Hutterer, F., Schaffner, F., Popper, H., Rosenthal, O., and Cooper, D. Y. 1973a. Microsomal metabolism of dimethylnitrosamine and the cytochrome P-450 dependency of its activation to a mutagen. Cancer Res. 33:2983–2986.Google Scholar
  6. Czygan, P., Greim, H., Garro, A. J., Hutterer, F., Rudick, J., Schaffner, F., and Popper, H. 1973b. Cytochrome P-450 content and the ability of liver microsomes from patients undergoing abdominal surgery to alter the mutagenicity of a primary and a secondary carcinogen. J. Natl. Cancer Inst. 51:1761–1764.Google Scholar
  7. Czygan, P., Greim, H., Garro, A., Schaffner, F., and Popper, H. 1974. The effect of dietary protein deficiency on the ability of isolated hepatic microsomes to alter the mutagenicity of a primary and a secondary carcinogen. Cancer Res. 34:119–123.PubMedGoogle Scholar
  8. Falk, H. L. 1971. Anticarcinogenesis-An alternative. Progr. Exptl. Tumor Res. 14:105–137.Google Scholar
  9. Kunz, W., Schaude, G., and Thomas, C. 1969. Die Beeinflussung der Nitrosamincarcinogenese durch Phenobarbital und Halogenkohlenwasserstoffe. Z. Krebsforsch. 72:291–304.PubMedCrossRefGoogle Scholar
  10. Magee, P. N., and Barnes, J. M. 1967. Carcinogenic nitroso compounds. Advan. Cancer Res. 10:163–256.CrossRefGoogle Scholar
  11. Magour, S., and Nievel, J. G. 1971. Effect of inducers of drug metabolizing enzymes on diethylnitrosamine metabolism and toxicity. Biochem. J. 123:8–9p.Google Scholar
  12. Mailing, H. V. 1971. Dimethylnitrosamine. Formation of mutagenic compounds by interaction with mouse liver microsomes. Mutation Res. 13:425–429.CrossRefGoogle Scholar
  13. Mannering, G. J. 1971. Properties of cytochrome P-450 as affected by environmental factors: Qualitative changes due to administration of polycyclic hydrocarbons. Metabolism 20:228–245.PubMedCrossRefGoogle Scholar
  14. Marshall, W. J., and McLean, A.E.M. 1969. The effect of oral phenobarbitone on hepatic microsomal cytochrome P-450 and demethylation activity in rats fed normal and low protein diets. Biochem. Pharmacol. 18:158–167.Google Scholar
  15. Marugami, M., Ito, N., Konishi, Y., Hsia, Y., and Farber, E. 1967. Influence of 3-methylcholanthrene on liver carcinogenesis in rats ingesting DL-ethionine, 3-methyl-4-dimethyl-aminoazobenzene, and 2-fluorenylacetamide. Cancer Res. 27: 2011–2019.PubMedGoogle Scholar
  16. McLean, A. E. M., and Marshall, A. 1971. Reduced carcinogenic effects of aflatoxin in rats given phenobarbitone. Brit. J. Exptl. Pathol. 52:322–329.Google Scholar
  17. McLean, A. E. M., and McLean, E. K. 1966. The effect of diet and 1, 1, 1-trichloro-2, 2-bis(p-chlorophenyl)ethane (DDT) on microsomal hydroxylating enzymes and on sensitivity of rats to carbon tetrachloride poisoning. Biochem. J. 100:564–571.PubMedGoogle Scholar
  18. Mgbodlie, M. U. K., Hayes, J. R., and Campbell, T. C. 1973. Effect of protein deficiency on the inducibility of the hepatic microsomal drug metabolizing enzyme system. II. Effect of enzyme kinetics and electron transport system. Biochem. Pharmacol. 22:1125–1132.CrossRefGoogle Scholar
  19. Miller, J. A., and Miller, E. C. 1965. Metabolism of drugs in relation to carcinogenicity. Ann. N. Y. Acad. Sci. 123:125–140.PubMedCrossRefGoogle Scholar
  20. Miller, E. C., and Miller, J. A. 1971. The mutagenicity of chemical carcinogens, pp. 83–119. In A. Hollaender (ed). Chemical Mutagens. Principles and Methods for Their Detection. Plenum Press, New York-London.Google Scholar
  21. Miller, E. C., Miller, J. A., Brown, R. R., and McDonald, J. C. 1958. On the protective action of certain polycyclic aromatic hydrocarbons against carcinogenesis by aminoazo dyes and 2-acetylaminofluorene. Cancer Res. 18:469–477.PubMedGoogle Scholar
  22. Peraino, C., Frey, R. J. M., and Staffelt, E. 1971. Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 31:1506–1512.PubMedGoogle Scholar
  23. Popper, H., Czygan, P., Greim, H., Schaffner, F., and Garro, A. J. 1973. Mutagenicity of primary and secondary carcinogens altered by normal and induced hepatic microsomes. Proc. Soc. Exp. Biol. and Med. 142:727–729.Google Scholar
  24. Rogers, A. E., and Newberne, P. M. 1971. Nutrition and aflatoxin carcinogenesis. Nature 229:62–63.PubMedCrossRefGoogle Scholar
  25. Shargel, L., and Mazel, P. 1968. Phenobarbital and 3-methylcholanthrene induction of microsomal azoreductase in riboflavin deficient rats. Fed. Proc. 27:302.Google Scholar
  26. Schoenthal, R. 1966. Carcinogenic activity of N-methyl-N’-nitro-N-nitrosoguanidine. Nature 209:726–727.CrossRefGoogle Scholar
  27. Tannenbaum, A., and Silverstone, H. 1953. Nutrition in relation to cancer. Advan. Cancer Res. 1:451–501.CrossRefGoogle Scholar
  28. Warburg, O. 1949. Heavy prosthetic groups and enzyme action. Oxford University Press, London.Google Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • Helmut Greim
    • 1
  • Peter Czygan
    • 1
  • Anthony J. Garro
    • 1
  • Ferenc Hutterer
    • 1
  • Fenton Schaffner
    • 1
  • Hans Popper
    • 1
  • Otto Rosenthal
    • 2
  • David Y. Cooper
    • 2
  1. 1.Stratton Laboratory for the Study of Liver Disease, Department of Pathology, and Department of MicrobiologyMount Sinai School of Medicine of The City University of New YorkNew YorkUSA
  2. 2.Harrison Department of Surgical ResearchUniversity of PennsylvaniaPhiladelphiaUSA

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