Cytochrome P-450 in the Activation and Inactivation of Carcinogens
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.
KeywordsLiver Microsome Human Liver Microsome Formaldehyde Formation Microsomal Preparation Hepatic Microsome
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- Falk, H. L. 1971. Anticarcinogenesis-An alternative. Progr. Exptl. Tumor Res. 14:105–137.Google Scholar
- 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
- 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
- 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
- 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
- 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
- Shargel, L., and Mazel, P. 1968. Phenobarbital and 3-methylcholanthrene induction of microsomal azoreductase in riboflavin deficient rats. Fed. Proc. 27:302.Google Scholar
- Warburg, O. 1949. Heavy prosthetic groups and enzyme action. Oxford University Press, London.Google Scholar