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. 1968 Nov;110(1):39–47. doi: 10.1042/bj1100039

Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate

P F Swann 1,*, P N Magee 1,*
PMCID: PMC1187106  PMID: 5722690

Abstract

1. N[14C]-Methyl-N-nitrosourea, [14C]dimethylnitrosamine, [14C]dimethyl sulphate and [14C]methyl methanesulphonate were injected into rats, and nucleic acids were isolated from several organs after various time-intervals. Radioactivity was detected in DNA and RNA, partly in major base components and partly as the methylated base, 7-methylguanine. 2. No 7-methylguanine was detected in liver DNA from normal untreated rats. 3. The specific radioactivity of 7-methylguanine isolated from DNA prepared from rats treated with [14C]dimethylnitrosamine was virtually the same as that of the dimethylnitrosamine injected. 4. The degree of methylation of RNA and DNA produced in various organs by each compound was determined, and expressed as a percentage of guanine residues converted into 7-methylguanine. With dimethylnitrosamine both nucleic acids were considerably more highly methylated in the liver (RNA, about 1% of guanine residues methylated; DNA, about 0·6% of guanine residues methylated) than in the other organs. Kidney nucleic acids were methylated to about one-tenth of the extent of those in the liver, lung showed slightly lower values and the other organs only very low values. N-Methyl-N-nitrosourea methylated nucleic acids to about the same extent in all the organs studied, the amount being about the same as that in the kidney after treatment with dimethylnitrosamine. In each case the RNA was more highly methylated than the DNA. Methyl methanesulphonate methylated the nucleic acids in several organs to about the same extent as N-methyl-N-nitrosourea, but the DNA was more highly methylated than the RNA. Dimethyl sulphate, even in toxic doses, gave considerably less methylation than N-methyl-N-nitrosourea in all the organs studied, the greatest methylation being in the brain. 5. The rate of removal of 7-methylguanine from DNA of kidneys from rats treated with dimethylnitrosamine was compared with the rate after treatment of rats with methyl methanesulphonate. No striking difference was found. 6. The results are discussed in connexion with the organ distribution of tumours induced by the compounds under study and in relation to the possible importance of alkylation of cellular components for the induction of cancer.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Axel R., Weinstein B., Farber E. Patterns of transfer RNA in normal rat liver and during hepatic carcinogenesis. Proc Natl Acad Sci U S A. 1967 Sep;58(3):1255–1260. doi: 10.1073/pnas.58.3.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brookes P., Lawley P. D. The reaction of mono- and di-functional alkylating agents with nucleic acids. Biochem J. 1961 Sep;80(3):496–503. doi: 10.1042/bj0800496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. CRADDOCK V. M., MAGEE P. N. METHYLATION OF LIVER DNA IN THE INTACT ANIMAL BY THE CARCINOGEN DIMETHYLNITROSAMINE DURING CARCINOGENESIS. Biochim Biophys Acta. 1965 Apr 19;95:677–678. doi: 10.1016/0005-2787(65)90526-5. [DOI] [PubMed] [Google Scholar]
  4. CRADDOCK V. M., MAGEE P. N. REACTION OF THE CARCINOGEN DIMETHYLNITROSAMINE WITH NUCLEIC ACIDS IN VIVO. Biochem J. 1963 Oct;89:32–37. doi: 10.1042/bj0890032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Craddock V. M., Villa-Trevino S., Magee P. N. Occurrence of 7-methylguanine in nucleic acids of rat liver. Biochem J. 1968 Mar;107(2):179–184. doi: 10.1042/bj1070179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DICKENS F., JONES H. E. Carcinogenic activity of a series of reactive lactones and related substances. Br J Cancer. 1961 Mar;15:85–100. doi: 10.1038/bjc.1961.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Druckrey H., Preussmann R., Ivankovic S., Schmähl D. Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z Krebsforsch. 1967;69(2):103–201. [PubMed] [Google Scholar]
  8. Druckrey H., Preussmann R., Nashed N., Ivankovic S. Carcinogene alkylierende Substanzen. I. Dimethylsulfat, carcinogene Wirkung an Ratten und wahrscheinliche Ursache von Berufskrebs. Z Krebsforsch. 1966;68(1):103–111. [PubMed] [Google Scholar]
  9. Graffi A., Hoffmann A., Schütt M. Nmethyl-N-nitrosourea as a strong topical carcinogen when painted on skin of rodents. Nature. 1967 May 6;214(5088):611–611. doi: 10.1038/214611a0. [DOI] [PubMed] [Google Scholar]
  10. Heath D. F. The decomposition and toxicity of dialkylnitrosamines in rats. Biochem J. 1962 Oct;85(1):72–91. doi: 10.1042/bj0850072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. KIDSON C., KIRBY K. S., RALPH R. K. ISOLATION CHARACTERISTICS OF RAPIDLY LABELLED RNA FROM NORMAL RAT LIVER. J Mol Biol. 1963 Sep;7:312–315. doi: 10.1016/s0022-2836(63)80010-8. [DOI] [PubMed] [Google Scholar]
  12. KIRBY K. S. A new method for the isolation of ribonucleic acids from mammalian tissues. Biochem J. 1956 Nov;64(3):405–408. doi: 10.1042/bj0640405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. LAWLEY P. D., BROOKES P. FURTHER STUDIES ON THE ALKYLATION OF NUCLEIC ACIDS AND THEIR CONSTITUENT NUCLEOTIDES. Biochem J. 1963 Oct;89:127–138. doi: 10.1042/bj0890127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lawley P. D., Brookes P., Magee P. N., Craddock V. M., Swann P. F. Methylated bases in liver acids from rats treated with dimethylnitrosamine. Biochim Biophys Acta. 1968 May 21;157(3):646–648. doi: 10.1016/0005-2787(68)90167-6. [DOI] [PubMed] [Google Scholar]
  15. Lee K. Y., Lijinsky W. Alkylation of rat liver RNA by cyclic N-nitrosamines in vivo. J Natl Cancer Inst. 1966 Oct;37(4):401–407. [PubMed] [Google Scholar]
  16. MAGEE P. N., BARNES J. M. The experimental production of tumours in the rat by dimethylnitrosamine (N-nitroso dimethylamine). Acta Unio Int Contra Cancrum. 1959;15(1):187–190. [PubMed] [Google Scholar]
  17. MAGEE P. N., FARBER E. Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo. Biochem J. 1962 Apr;83:114–124. doi: 10.1042/bj0830114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. MAGEE P. N., HULTIN T. Toxic liver injury and carcinogenesis. Methylation of proteins of rat-liver slices by dimethylnitrosamine in vitro. Biochem J. 1962 Apr;83:106–114. doi: 10.1042/bj0830106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MARKHAM R., SMITH J. D. The structure of ribonucleic acid. I. Cyclic nucleotides produced by ribonuclease and by alkaline hydrolysis. Biochem J. 1952 Dec;52(4):552–557. doi: 10.1042/bj0520552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. MIZRAHI I. J., EMMELOT P. ON THE MODE OF ACTION BY WHICH THE CARCINOGEN DIMETHYLNITROSAMINE INHIBITS PROTEIN SYNTHESIS IN THE LIVER. Biochim Biophys Acta. 1964 Oct 16;91:362–364. doi: 10.1016/0926-6550(64)90271-3. [DOI] [PubMed] [Google Scholar]
  21. Magee P. N., Barnes J. M. Carcinogenic nitroso compounds. Adv Cancer Res. 1967;10:163–246. doi: 10.1016/s0065-230x(08)60079-2. [DOI] [PubMed] [Google Scholar]
  22. PITOT H. C., HEIDELBERGER C. METABOLIC REGULATORY CIRCUITS AND CARCINOGENESIS. Cancer Res. 1963 Nov;23:1694–1700. [PubMed] [Google Scholar]
  23. REINER B., ZAMENHOF S. Studies on the chemically reactive groups of deoxyribonucleic acids. J Biol Chem. 1957 Sep;228(1):475–486. [PubMed] [Google Scholar]
  24. Shank R. C. Effect of dimethylnitrosamine on enzyme induction in rat liver. Biochem J. 1968 Jul;108(4):625–631. doi: 10.1042/bj1080625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shank R. C., Magee P. N. Similarities between the biochemical actions of cycasin and dimethylnitrosamine. Biochem J. 1967 Nov;105(2):521–527. doi: 10.1042/bj1050521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Swann P. F. Methylation in vivo of guanine in the nucleic acids of rat testes by methyl methane sulphonate. Nature. 1967 May 27;214(5091):918–919. doi: 10.1038/214918a0. [DOI] [PubMed] [Google Scholar]
  27. Swann P. F. The rate of breakdown of methyl methanesulphonate, dimethyl sulphate and N-methyl-N-nitrosourea in the rat. Biochem J. 1968 Nov;110(1):49–52. doi: 10.1042/bj1100049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Villa-Treviño S. A possible mechanism of inhibition of protein synthesis by dimethylnitrosamine. Biochem J. 1967 Nov;105(2):625–631. doi: 10.1042/bj1050625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. WALPOLE A. L. Carcinogenic action of alkylating agents. Ann N Y Acad Sci. 1958 Apr 24;68(3):750–761. doi: 10.1111/j.1749-6632.1958.tb42638.x. [DOI] [PubMed] [Google Scholar]

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