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Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver

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Summary

Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation.

Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

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Abbreviations

O6-alkylGua:

O6-alkylguanine

O6-MeGua:

O6-methylguanine

7-MeGua:

7-methylguanine

AAP:

alkyl acceptor protein

S-MeCys:

S-methylcysteine

NDMA:

dimethylnitrosamine

NDEA:

diethylnitrosamine

NMBzA:

N-methyl-benzylnitrosamine

NMPhA:

N-methyl-phenylnitrosamine

EDTA:

ethylene diaminetetraacetic acid

DTT:

dithiothreitol

PCA:

perchloric acid

References

  1. Anderson D, Blowers SD, Craddock VM (1985) The effects of S9 mix from rat esophageal carcinogen N-nitroso-N-methylaniline in the Salmonella typhimurium assay. Mutat Res 142:13–18

  2. Araki A, Muramatsu M, Matsushima T (1984) Comparison of mutagenicities of N-nitrosamines on Salmonella typhymurium TA 100 and Escherishia coli WP2 UVRA/PK M101 using rat and hamster S9. Gann 75:8–16

  3. Bertalanffy FD (1967) Comparison of mitotic rates in normal renewing and neoplastic cell populations. In: Morgan JF (ed) 7th Canadian Cancer Conference. Pergamon Press, pp 65–83

  4. Bertram B, Frei E, Wiessler M (1985) Influence of disulfiram on glutathione, glutathione-S-transferase, and on nitrosamine-dealkylases of liver, kidney and esophagus of the rat. Biochem Pharmacol 34:387–388

  5. Bogden JM, Eastman A, Bresnick E (1981) A system in mouse liver for the repair of O6-methylguanine lesions in methylated DNA. Nucleic Acids Res 9:3089–3103

  6. Burton K (1956) A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of DNA. Biochem J 62:315–323

  7. Craddock VM (1976) Cell proliferation and experimental liver cancer. In: Warwick GP, Cameron H, Linsell CA (eds) Liver cell cancer. Elsevier Press, Amsterdam, pp 153–201

  8. Craddock VM, Henderson AR (1977) De novo replication and repair replication of DNA during diethylnitrosamine-induced carcinogenesis. Cancer Lett 3:277–284

  9. Craddock VM, Henderson AR (1984) Repair and replication of DNA in rat and mouse tissues in relation to cancer induction by N-nitroso-N-alkyl-ureas. Chem Biol Interact 52:223–231

  10. Craddock VM, Henderson AR, Gash S (1982) Nature of the constitutive and induced mammalian O6-methylguanine DNA repair enzyme. Biochem Biophys Res Commun 107:546–553

  11. Craddock VM, Henderson AR, Gash S (1984) Repair and replication of DNA in rat brain and liver during foetal and post-natal development, in relation to nitroso-alkyl-urea induced carcinogenesis. J Can Res Clin Onc 108:30–35

  12. Druckrey H, Preussmann R, Blum G, Ivankovic S, Afkham T (1963) Induction of esophageal cancer with unsymmetrical nitrosamines. Naturwissenschaften 50:100–101

  13. Fong LYY, Sivak A, Newberne PM (1978) Zinc deficiency and methyl-benzyl-nitrosamine-induced esophageal cancer in rats. J Natl Cancer Inst 61:145–150

  14. Giles KW, Myers A (1965) An improved diphenylamine method for estimation of DNA. Nature 206:93

  15. Gray R, Peto R, Brantom P, Grasso P (1984) Dose and time relationships for nitrosamine carcinogenesis among inbred Colworth rats. In: O'Neill IK, Miller CT, von Borstel RC, Long JE, Bartsch H (eds) N-Nitroso compounds: occurrence and biological effects and relevance to human cancer. IACR Scientific Publication No 57, pp 627–665

  16. Hodgson RM, Wiessler M, Kleihues P (1980) Preferential methylation of target organ DNA by the oesophageal carcinogen N-nitrosomethylbenzylamine. Carcinogenesis 1:861–866

  17. Iizuka T, Ichimura S, Kawachi T (1978) Autoradiography and organ distribution of N-methyl N-nitrosobenzylamine. Gann 69:487–492

  18. Kleihues P, Margison GP (1976) Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA. Nature 259:153–155

  19. Lawley PD, Thatcher C (1970) Methylation of DNA in cultured mammalian cells by N-methyl-N′-nitro-N-nitrosoguanidine. Biochem J 116:693–707

  20. Lindahl T (1982) DNA repair enzymes. Ann Rev Biochem 51:61–87

  21. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

  22. Magee PN, Montesano R, Preussmann R (1982) N-Nitrosocompounds and related carcinogens. In: Searle CE (ed) Chemical carcinogens. ACS Monorgraph 173:491–625

  23. Margison GP (1982) Chronic or acute administration of various dialkylnitrosamines enhances the removal of O6-methylguanine from rat liver DNA in vivo. Chem Biol Interact 38:189–201

  24. Margison GP, O'Connor PJ (1979) Nucleic acid modification by N-nitroso compounds. In: Grover PL (ed) Chemical carcinogens and DNA. CRC Press, vol. 1, pp 111–159

  25. Michejda CJ, Kroeger Koepke MB, Koepke SR, Magee PN, Chu C (1982) Nitrogen formation during in vivo and in vitro metabolism of N-nitrosamines. In: Nitrosamines and human cancer. Banbury Report 12, Cold Spring Harbor Laboratory, 69–85

  26. Neurath GB, Dunger M, Pein FG, Ambrosius D, Schrieber O (1977) Primary and secondary amines in the human environment. Food Cosmet Toxicol 15:275–282

  27. O'Brien TG (1980) Tumor promoters and polyamines. In: Gaugas JM (ed) Polyamines in biomedical reasearch. Wiley, pp 237–253

  28. Pegg AE (1978a) Dimethylnitrosamine inhibits enzymatic removal of O6-methylguanine from DNA. Nature 274:182–184

  29. Pegg AE (1978b) Enzymatic removal of O6-methylguanine from DNA by mammalian cell extracts. Biochem Biophys Res Commun 84:166–173

  30. Pegg AE (1984) Properties of the O6-alkylguanine DNA repair system of mammalian cells. In: N-Nitroso compounds: occurrence, biological effects and relevance to human cancer. IARC Scientific Publication No 57, pp 575–580

  31. Pegg AE, Perry W (1981) Stimulation of transfer of methyl groups from O6-methylguanine in DNA to protein by rat liver extracts in response to hepatotoxins. Carcinogenesis 2:1195–1200

  32. Pegg AE, Lijinsky W (1984) Saturation of repair system for O6-methylguanine in rat liver DNA by pretreatment with cyclic nitrosamines. Chem Biol Interact 51:365–370

  33. Pegg AE, Perry W, Bennett RA (1981) Effect of partial hepatectomy on removal of O6-methylguanine from alkylated DNA by rat liver extracts. Biochem J 167:195–201

  34. Rajewsky MF (1972) Proliferative parameters of mammalian cell systems and their role in tumor growth and carcinogenesis. Z Krebsforsch 78:12–30

  35. Saito S, Itano HA (1981) βMesophenylbiliverdin IXα and N-phenylprotoporhyrin IX, products of the reaction of phenylhydrazine with oxyhemoproteins. Proc Natl Acad Sci USA 78:5508–5512

  36. Segerback D, Calleman CJ, Ehrenberg L, Lofroth G, Ostermann-Golkar S (1978) Evaluation of genetic risks of alkylating agents. IV. Quantitative determination of alkylated amino acids in haemoglobin as a measure of the dose after treatment of mice with methyl methanesulphonate. Mutat Res 49:71–82

  37. Silinskas KC, Zucker PF, Labruc GE, Archer MC (1984) Formation of O6-methylguanine in regenerating rat liver by methyl-benzylnitrosamine is not sufficient for initiation of preneoplastic foci. Carcinogenesis 5:541–542

  38. Swenberg JA, Dyroff MC, Bedell MA, Popp JA, Huh N, Kirstein V, Rajewsky M (1984) O4-Ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine. Proc Natl Acad Sci (USA) 18:1692–1695

  39. Turberville C, Craddock VM (1971) Methylation of nuclear proteins by dimethylnitrosamine and by methionine in the rat in vivo. Biochem J 124:725–739

  40. Wakabayashi K, Nagao M, Kawachi T, Sugimura T (1982) Mechanism of appearance of mutagenicity of N-nitrosodiphenylamine with norharman. In: Bartsch H, Castegaro M, O'Neill IK, Okada M (eds) N-Nitroso compounds: occurrence and biological effects. IARC Scientific Publications No 41, pp 695–707

  41. Yang CS (1980) Research on esophageal cancer: a review. Cancer Res 40:2633–2644

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Correspondence to Valda M. Craddock.

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Craddock, V.M., Henderson, A.R. Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver. J Cancer Res Clin Oncol 111, 229–236 (1986). https://doi.org/10.1007/BF00389238

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Key words

  • N-Nitrosamines
  • O6-Alkylguanine
  • DNA-methyl transferase
  • Oesophageal cancer