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Chemical mutagens: alkylating agents. II: Chemistry. Molecular analysis of mutants. Influence of cellular processes. Kinetics

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Mutation research

Abstract

Biological alkylating agents are chemicals that transfer alkyl groups to biologically important macromolecules under physiological conditions. Ross (1) has reviewed their general chemistry; Lawley (2) their reactions with nucleic acids. Table 16.1 lists the main classes of alkylating agent; each class is represented by one or several well-known mutagens. Cutting across this classification by structural group are differences in two properties whose role in mutagenicity has been much discussed. One is the type of alkyl group transferred, whether it is, e. g. a methyl or ethyl group or a more complex one like — CH2 COCH3. The other is the number of alkyl groups that a single molecule can donate. This property is called the ‘functionality’ of the compound. Thus, among the nitrogen mustards, H2N (CH2CH2Cl) is monofunctional, HN (CH2CH2Cl)2 is bifunctional, and N (CH2CH2Cl)3 is trifunctional. The term polyfunctional may be used for all compounds whose functionality is greater than one. It should be noted that the degree of functionality cannot be inferred simply from the number of alkyl groups carried by a compound. The alkyl alkanesulphonates, for example, are mono-functional, EMS donating only its ethyl group and MMS only one of its two methyl groups.

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References

  1. Ross, W.C.J. (1962), ‘Biological Alkylating Agents’, Butterworths, London.

    Google Scholar 

  2. Lawley, P.D. (1966), ‘Effects of some chemical mutagens and carcinogens on nucleic acids’, Progr. Nucleic Acid Res. Mol. Biol. 5, 89–131.

    Article  CAS  Google Scholar 

  3. Magee, P.N. and Farber, E. (1962), ‘Toxic liver injury and carcinogenesis. Methylation of rat liver nucleic acids by dimethylnitrosamine in vivo’, Biochem. J. 83, 114–124.

    PubMed  CAS  Google Scholar 

  4. Mailing, H.V. (1971), ‘Dimethylnitrosamine: formation of compounds by interaction with mouse liver microsomes’, Mutation Res. 13, 425–429.

    Article  Google Scholar 

  5. Iyer, V.N. and Szybalski, W. (1964), ‘Mitomycins and porfiromycin: Chemical mechanism of activation and cross-linking of DNA’, Science 145, 55–58.

    Article  PubMed  CAS  Google Scholar 

  6. Lawley, P.D. and Brookes, P. (1974), Alkylation of nucleic acids and mutagenesis, in Molecular and Environmental Aspects of Mutagenesis’, L. Prakash et al. (ed.), Thomas, Springfield, Ill., pp 17–31.

    Google Scholar 

  7. Lawley, P.D. and Brookes, P. (1963), ‘Further studies on the alkylation of nucleic acids and their constituent nucleotides’, Biochem. J. 89, 127–138.

    PubMed  CAS  Google Scholar 

  8. Loveless, A. (1959), ‘The influence of radiomimetic substances on deoxyribonucleic acid synthesis and function in Escherichia coli/ phage systems. III. Mutation of T2 bacteriophage as a consequence of alkylation in vitro: the uniqueness of ethylation’, Proc. Roy. Soc. Lond. 150, 497–508.

    Article  CAS  Google Scholar 

  9. Kølmark, G. (1956), ‘Mutagenic properties of certain esters of inorganic acids investigated by the Neurospora back-mutation test’, C.R. Labor. Carlsberg. Ser. Physiol. 26, 206–220.

    Google Scholar 

  10. Loprieno, N. (1966), ‘Differential response of Schizosaccharomyces pombe to ethyl methanesulfonate and methyl methanesulfonate’, Mutation Res. 3, 486–493.

    Article  CAS  Google Scholar 

  11. Strauss, B.S. (1961), ‘Specificity of the mutagenic action of the alkylating agents’, Nature 191, 730–731.

    Article  CAS  Google Scholar 

  12. Rhaese, H.Y. and Boetker, N.K. (1973), ‘The molecular basis of mutagenesis by methyl and ethyl methanesulfonates’, Eur. J. Biochem. 32, 166–172.

    Article  PubMed  CAS  Google Scholar 

  13. Watson, W.A.F. (1964), ‘Evidence of an essential difference between the genetical effects of mono-and bifunctional agents’, Zeitschr. Vererb. Lehre 95, 374–378.

    CAS  Google Scholar 

  14. Watson, W.A.F. (1966), ‘Further evidence of an essential difference between the genetical effects of mono-and bifunctional alkylating agents’, Mutation Res., 3, 455–457.

    Article  PubMed  CAS  Google Scholar 

  15. Šram, R.J. (1970), ‘The effect of storage on the frequency of translocations in Drosophila melanogaster’, Mutation Res. 9, 243–244.

    Article  PubMed  Google Scholar 

  16. Laurence, D.Y.R. (1963), ‘Chain breakage of deoxyribonucleic acid following treatment with low doses of sulphur mustard’, Proc. Roy. Soc. Lond. A 271, 520–530.

    Article  Google Scholar 

  17. Flamm, W.G., Bernheim, N.Y. and Fishbein, L. (1970), On the existence of intrastrand crosslinks in DNA alkylated with sulphur mustard’, Biochim. Biophys. Acta 224, 657–659.

    Article  PubMed  CAS  Google Scholar 

  18. Lawley, P.D., Lethbridge, J.H., Edwards, P.A. and Shooter, K.V. (1969), ‘Inactivation of bacteriophage T7 by mono-and difunctional sulphur mustards in relation to crosslinking and depurination of bacteriophage DNA’, J. Mol. Biol. 39, 181–198.

    Article  PubMed  CAS  Google Scholar 

  19. Smith, H.H. and Lotfy, T. A. (1955), ‘Effects of β-propiolactone and Ceepryn on chromosomes of Vicia and Allium’, Amer. J. Bot. 42, 750–758.

    Article  CAS  Google Scholar 

  20. Swanson, C.P. and Merz, T. (1959), ‘Factors influencing the effect of β-propiolactone on chromosomes of Vicia faba’, Science 129, 1364–1365.

    Article  PubMed  CAS  Google Scholar 

  21. Kimball, R.F. (1965), ‘The induction of reparable premutational damage in Paramecium aurelia by the alkylating agent triethylene melamine’, Mutation Res. 2, 413–425.

    Article  PubMed  CAS  Google Scholar 

  22. Kølmark, H.G. and Kilbey, B.J. (1968), ‘Kinetic studies of mutation induction by epoxides in Neurospora crassa’, Molec. Gen. Genetics 101, 89–98.

    Article  Google Scholar 

  23. Nakao, Y. and Auerbach, C. (1961), ‘Test of a possible correlation between cross-linking and chromosome breaking abilities of chemical mutagens’, Zeitschr. Vererb. Lehre. 92, 457–461.

    CAS  Google Scholar 

  24. Slizynska, H. (1973), ‘Cytological analysis of storage effects on various types of complete and mosaic change induced in Drosophila chromosomes by some chemical mutagens’, Mutation Res. 19, 199–213.

    Article  PubMed  CAS  Google Scholar 

  25. Ehrenberg, L. and Gustafsson, A. (1957), On the mutagenic action of ethylene oxide and diepoxybutane in barley’, Hereditas 43, 595–602.

    Article  Google Scholar 

  26. Rapoport, J.A., Zoz, N.N., Makarova, S.I. and Salnikova, T.V. (Eds.) (1966). ‘Super-mutagens’, Nauka, Moscow (in Russian).

    Google Scholar 

  27. Bautz, E. and Freese, E. (1960), ‘On the mutagenic effect of alkylating agents’, Proc. Nat. Acad. Sci. U.S.A. 46, 1585–1594.

    Article  CAS  Google Scholar 

  28. Krieg, D.R. (1963), ‘Ethyl methanesulfonate-induced reversion of bacteriophage T4 rII mutants’, Genetics 48, 561–580.

    PubMed  CAS  Google Scholar 

  29. Tessman, I., Poddar, R.K. and Kumar, S. (1964), ‘Identification of the altered bases in mutated single-stranded DNA. I. In vitro mutagenesis by hydroxylamine, ethyl methane-sulfonate and nitrous acid’, J. Mol. Biol. 9, 352–363.

    Article  PubMed  CAS  Google Scholar 

  30. Baker, R. and Tessman, I. (1968), ‘Different mutagenic specificities in phages S13 and T4: in vivo treatment with N-methyl-N-nitro-N-nitroso-guanidine’, J. Mol. Biol. 35, 439–448.

    Article  CAS  Google Scholar 

  31. Salganik, R.I. (1972), ‘Some possibilities of mutation control concerned with local increase of DNA sensitivity to chemical mutagens’, Biol. Zbl. 91, 49–59.

    CAS  Google Scholar 

  32. Singer, R. and Fraenkel-Conrat, H. (1969), ‘The role of conformation in chemical mutagenesis’, Progr. Nucleic Acid Res. Mol. Biol., 9, 1–29.

    Article  CAS  Google Scholar 

  33. Singer, B., Fraenkel-Conrat, H., Greenberg, J. and Michelson, A.M. (1968), ‘Reaction of nitrosoguanidine (N-methyl-N’-nitro-N-nitrosoguanidine) with tobacco mosaic virus and its RNA’, Science 160, 1235–1236.

    Article  PubMed  CAS  Google Scholar 

  34. Osborn, M., Person, S., Phillips, S. and Funk, F. (1967), ‘A determination of mutagen specificity in bacteria using nonsense mutants of bacteriophage T4’, J. Mol. Biol. 26, 437–448.

    Article  PubMed  CAS  Google Scholar 

  35. Smith, J.D., Barnett, L., Brenner, S. and Russell, R.L. (1970). ‘More mutant tyrosine transfer ribonucleic acids’, J. Mol. Biol. 54, 1–14.

    Article  PubMed  CAS  Google Scholar 

  36. Schwartz, N.M. (1963), ‘Nature of ethyl methanesulfonate induced reversions of lac− mutants of Escherichia coli’, Genetics 48, 1357–1375.

    PubMed  CAS  Google Scholar 

  37. Eisenstark, A., Eisenstark, R. and Van Sickle, R. (1965), ‘Mutation of Salmonella typhimurium by nitrosoguanidine’, Mutation Res. 2, 1–10.

    Article  PubMed  CAS  Google Scholar 

  38. Mailing, H.V. and de Serres, F.J. (1968), ‘Identification of genetic alterations induced by ethyl methanesulfonate in Neurospora crassa’, Mutation Res. 6, 181–193.

    Article  Google Scholar 

  39. Mailing, H.V. and de Serres, F.J. (1970), ‘Genetic effects of N-methyl-N-nitro-N-nitrosoguanidine in Neurospora crassa’, Molec. Gen. Genetics 106, 195–207.

    Article  Google Scholar 

  40. Prakash, L. and Sherman, F. (1973), ‘Mutagenic specificity: Reversion of iso-1-cytochrome c mutants of yeast’, J. Mol. Biol. 79, 65–82.

    Article  PubMed  CAS  Google Scholar 

  41. Bryson, V. (1948), ‘Reciprocal cross resistance of adapted Escherichia coli to nitrogen mustard and ultraviolet light’, Genetics 33, 99.

    PubMed  CAS  Google Scholar 

  42. Reiter, H. and Strauss, B. (1965), ‘Repair of damage induced by a monofunctional alkylating agent in a transformable ultraviolet-sensitive strain of Bacillus subtilis’, J. Mol. Biol. 14, 179–194.

    Article  PubMed  CAS  Google Scholar 

  43. Papirmeister, B. and Davison, C.L. (1964), ‘Elimination of sulphur mustard induced products from DNA of Escherichia coli’, Biochem. Biophys. Res. Comm. 17, 608–617.

    Article  CAS  Google Scholar 

  44. Lawley, P.D. and Brookes, P. (1965), ‘Molecular mechanism of the cytotoxic action of difunctional alkylating agents and of resistance to this action’, Nature 206, 480–483.

    Article  PubMed  CAS  Google Scholar 

  45. Crathorn, A.R. and Roberts, J.J. (1966), ‘Mechanism of the cytotoxic action of alkylating agents in mammalian cells and evidence for the removal of alkylated groups from deoxyri-bonucleic acid’, Nature 211, 150–153.

    Article  PubMed  CAS  Google Scholar 

  46. Cerdá-Olmedo, E. and Hanawalt, P.C. (1967), ‘Repair of DNA damaged by N-methyl-N’-nitro-N-nitrosoguanidine in Escherichia coli’, Mutation Res. 4, 369–671.

    Article  PubMed  Google Scholar 

  47. Strauss, G., Coyle, M. and Robbins, M. (1968), ‘Alkylation damage and its repair’, Cold Spring Harbor Symp. Quant. Biol. 33, 277–287.

    Article  PubMed  CAS  Google Scholar 

  48. Veleminsky, J., Zadraxil, S., Pokorny, V., Gichner, T. and Svachulova, J. (1973), ‘Repair of single-strand breaks and fate of N-7-methylguanine in DNA during the recovery from genetical damage induced by N-methyl-N-nitrosourea in barley seeds’, Mutation Res. 17, 49–58.

    Article  CAS  Google Scholar 

  49. Roberts, J.J. and Sturrock, J.E. (1973), ‘Enhancement by caffeine of N-methyl-N-nitrosourea-induced mutations and chromosome aberrations in Chinese hamster cells’, Mutation Res. 20, 243–255.

    Article  PubMed  CAS  Google Scholar 

  50. Roberts, J.J., Sturrock, J.E. and Ward, K.N. (1974), ‘The enhancement by caffeine of alkylation-induced cell death, mutations and chromosomal aberrations in Chinese hamster cells, as a result of inhibition of post-replication DNA repair’, Mutation Res. 26, 129–143.

    Article  PubMed  CAS  Google Scholar 

  51. Swietlinska, Z. and Zuk, J. (1974), ‘Effect of caffeine on chromosome damage induced by chemical mutagens and ionizing radiation in Vicia faba and Secale cereale’, Mutation Res. 26, 89–97.

    Article  CAS  Google Scholar 

  52. Kondo, S., Ichikawa, H., Iwo, K. and Kato, T. (1970), ‘Base change mutagenesis and prophage induction in strains of E. coli with different repair capacities’, Genetics 66, 187–217.

    PubMed  CAS  Google Scholar 

  53. Evans, H.J. (1967), ‘Repair and recovery at chromosome and cellular levels: similarities and differences’, Brookhaven Symp. Biol. 20, 111–133.

    Google Scholar 

  54. Cattanach, B.M. (1957), ‘Induction of translocations in mice by triethylene mélanine’, Nature 180, 1364–1365.

    Article  PubMed  CAS  Google Scholar 

  55. Drake, J.W. and Greening, E.O. (1970), ‘Suppression of chemical mutagenesis in bateriophage T4 by genetically modified DNA polymerases’, Proc. Nat. Acad. Sci. U.S.A. 66, 823–829.

    Article  CAS  Google Scholar 

  56. CerdCerdá-Olmedo, E., Hanawalt, P.C. and Guerola, N. (1968), ‘Mutagenesis of the replication point by nitrosoguanidine: Map and pattern of replication of the Escherichia coli chromosome’, J. Mol. Biol. 33, 705–719.

    Article  Google Scholar 

  57. Guerola, N., Ingraham, J.L. and CerdCerdá-Olmedo, E. (1971), ‘Induction of closely linked multiple mutations by nitrosoguanidine’, Nature New Biology, 230, 122–125.

    Article  PubMed  CAS  Google Scholar 

  58. Bresler, S.E., Kalinin, V.L. and Sukhodolova, A.T. (1972), ‘Action of supermutagens on the transforming DNA of B. subtilis’, Mutation Res. 15, 101–112.

    Article  PubMed  CAS  Google Scholar 

  59. Browning, L.S. (1969), ‘The mutational spectrum produced in Drosophila by N-methyl-NN’-nitro-N-nitrosoguanidine’, Mutation Res. 8, 157–164.

    Article  PubMed  CAS  Google Scholar 

  60. Brock, R.D. (1971), ‘Differential mutation of the β-galactosidase gene of Escherichia coli.’, Mutation Res. 11, 181–186.

    PubMed  CAS  Google Scholar 

  61. Kimball, R.F. (1970), ‘Studies on the mutagenic action of N-methyl-NN’-nitro-N-nitrosoguanidine in Paramecium aurelia with emphasis on repair processes’, Mutation Res. 9, 261–271.

    Article  PubMed  CAS  Google Scholar 

  62. Asato, Y. and Folsome, C.E. (1970), ‘Temporal genetic mapping of the blue-green alga Anacystis nidulans’, Genetics, 65, 407–419.

    PubMed  CAS  Google Scholar 

  63. Altenbern, R.A. (1973), ‘Gene order in species of Staphylococcus’, Canad. J. Microbiol. 19, 105–108.

    Article  CAS  Google Scholar 

  64. Gillham, N.W. (1965), ‘Induction of chromosomal and nonchromosomal mutations in Chlamydomonas reinhardi with N-methyl-NN’-nitro-N-nitrosoguanidine’, Genetics 52, 529–537.

    PubMed  CAS  Google Scholar 

  65. Dawes, I.W. and Carter, B.L.A. (1974), ‘Nitrosoguanidine mutagenesis during nuclear and mitochondrial gene replication’, Nature 250, 709–712.

    Article  PubMed  CAS  Google Scholar 

  66. Corran, J. (1968), ‘The induction of supersuppressor-mutants of B. subtilis by ethylmethanesulphonate and the posttreatment modification of mutation yield’, Molec. Gen. Genetics 103, 42–57.

    Article  CAS  Google Scholar 

  67. Johnson, J.M. and Ruddon, R.W. (1967), ‘Interaction of nitrogen mustard with polyribonucleotides, ribosomes and enzymes involved in protein synthesis in a cell-free system’, Molec. Pharmacol. 3, 195–203.

    CAS  Google Scholar 

  68. Reid, B.R. (1968), ‘Selective inactivation of E. coli t-RNA by ethyleneimine’, Biochem. Biophys. Res. Comm. 33, 627–635.

    Article  PubMed  CAS  Google Scholar 

  69. Chandra, P., Wacker, A., Sussmuth, R. and Lingens, F. (1967), ‘Wirkung von 1-Nitroso-3-nitro-1-methyl-guanidin auf die Matrizenaktivität der Polynucleotide bei der zellfreien Proteinsynthese’. Zeitschr. Naturforsch. 22b, 512–517.

    Google Scholar 

  70. Bresler, S.E., Kalinin, V.L. and Perumov, D.A. (1968), ‘Inactivation and mutagenesis in isolated DNA. II Kinetics of mutagenesis and efficiency of different mutagens’, Mutation Res. 5, 1–14.

    Article  PubMed  CAS  Google Scholar 

  71. Nasrat, G.E., Kaplan, W.D. and Auerbach, C. (1954), ‘A quantitative study of mustard-gas induced chromosome breaks and rearrangements in Drosophila melanogaster’, Zeitschr. indukt. Abst. Vererb. Lehre 86, 249–262.

    CAS  Google Scholar 

  72. Turtoczky, J. and Ehrenberg, L. (1969), ‘Reaction rates and biological action of alkylating agents’, Mutation Res. 8, 229–238.

    Article  PubMed  CAS  Google Scholar 

  73. Tarmy, E.M., Venitt, S. and Brookes, P. (1973), ‘Mutagenicity of the carcinogen 7-bromomethylbenz-(a) anthracene’, Mutation Res. 19, 153–160.

    Article  PubMed  CAS  Google Scholar 

  74. Auerbach, C. and Ramsay, D. (1968), ‘Analysis of a case of mutagen specificity in Neurospora crassa. I. Dose-response curves’, Molec. Gen. Genetics 103, 72–104.

    Article  CAS  Google Scholar 

  75. Kilbey, B. (1973), ‘The manipulation of mutation induction kinetics in Neurospora crassa’, Molec. Gen. Genetics 123, 73–76.

    Article  CAS  Google Scholar 

  76. Auerbach, C. and Ramsay, D. (1973), ‘Analysis of the storage effect of diepoxybutane (DEB)’, Mutation Res. 18, 129–141.

    Article  CAS  Google Scholar 

  77. Auerbach, C. and Ramsay, D. (1970), ‘Analysis of a case of mutagen specificity in Neurospora crassa. III. Fractionated treatment with diepoxybutane (DEB)’, Molec. Gen. Genetics 109, 285–291.

    Article  CAS  Google Scholar 

  78. Auerbach, C. and Ramsay, D. (1970) ‘Analysis of a case of mutagen specificity in Neurospora crassa. II. Interaction between treatments with diepoxybutane (DEB) and ultraviolet light’, Molec. Gen. Genetics 109, 1–17.

    Article  CAS  Google Scholar 

  79. Rannug, J.U. (1971), ‘Photoreactivation of mutational damage produced by the interaction of DEB and UV in Neurospora’, Molec. Gen. Genetics 111, 194–196.

    Article  CAS  Google Scholar 

  80. Worthy, T.E. and Epier, J.L. (1973), ‘Biochemical basis of radiation-sensitivity in mutants of Neurospora crassa’, Mutation Res. 19, 167–173.

    Article  PubMed  CAS  Google Scholar 

  81. Paterson, H.F. (1974), ‘Investigations into a reversal of diepoxybutane specificity in Neurospora crassa’, Mutation Res. 25, 411–413.

    Article  PubMed  CAS  Google Scholar 

  82. Allison, M. (1969), ‘Mutagen specificity at the ad-3A and inositol loci in Neurospora crassa’, Mutation Res. 7, 141–154.

    Article  PubMed  CAS  Google Scholar 

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  1. Institute of Animal Genetics, University of Edinburgh, UK

    Charlotte Auerbach F.R.S. (Professor Emeritus)

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Auerbach, C. (1976). Chemical mutagens: alkylating agents. II: Chemistry. Molecular analysis of mutants. Influence of cellular processes. Kinetics. In: Mutation research. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-3103-0_16

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  • DOI: https://doi.org/10.1007/978-1-4899-3103-0_16

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