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Computational Study of Mutagen X

  • Cho, Seung-Joo (Life Science Division, Korea Institute of Science and Technology)
  • Published : 2003.06.20

Abstract

Mutagen X (MX), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone is one of the most potent directing acting mutagen ever tested in SAL TA100 assay. Although MX analogues have been synthesized, tested for mutagenicity and modeled by structure-activity relationship (SAR) methods, the mechanism of interaction of these compounds with DNA to produce their remarkable mutagenic potency remains unresolved. MX exists as an equilibrium mixture of both ring and open form in water. This equilibrium is very fast for Ames test. Because the mixture is not separable by experimental methods, it is not clear which one is really responsible for the observed mutagenicity. There have been many debates that which one is really responsible for the observed mutagenicity. We used ab initio methods for the MX analogues. It seems both ring and open form could react with DNA bases as electrophiles. However, every open form has consistently lower LUMO energy than corresponding ring form. It is reasonable to assume that the major reaction will go through via open form for MX analogues. This suggest that the open form is more likely really mutagenic.

References

  1. Isomaa, B.; Holmstrom, T. H.; Lilius, H.; Franzen, R.; Kronberg, L. Toxicology 1995, 100, 69-77. https://doi.org/10.1016/0300-483X(95)03067-P
  2. Jansson, K.; Maki-Paakkanen, J.; Vaittinen, S. L.; Vartiainen, T.;Komulainen, H.; Tuomisto, J. Mutat. Res. 1993, 299, 25-28. https://doi.org/10.1016/0165-1218(93)90115-T
  3. Teramoto, S.; Takahashi, K.; Kikuta, M.; Kobayashi, H. J. Toxicol. Environ. Health 1998, 53, 607-614. https://doi.org/10.1080/009841098159060
  4. Munter, T.; Le Curieux, F.; Sjoholm, R.; Kronberg, L. Chem. Res. Toxicol. 1998, 11, 226-233. https://doi.org/10.1021/tx970195x
  5. Franzen, R.; Goto, S.; Tanabe, K.; Morita, M. Mutat. Res. 1998,417, 31-37. https://doi.org/10.1016/S1383-5718(98)00092-8
  6. Kronberg, L.; Christman, R. F. The Science of the Total Environment1989, 81, 219. https://doi.org/10.1016/0048-9697(89)90128-9
  7. Tuppurainen, K. SAR QSAR Environ. Res. 1997, 7, 281-286. https://doi.org/10.1080/10629369708039134
  8. Tuppurainen, K. Chemosphere 1999, 38, 3015-3030. https://doi.org/10.1016/S0045-6535(98)00503-7
  9. Tuppurainen, K.; Lotjonen, S. Mutat. Res. 1993, 287, 235-241. https://doi.org/10.1016/0027-5107(93)90016-9
  10. Tuppurainen, K.; Lotjonen, S.; Laatikainen, R.; Vartiainen, T.Mutat. Res. 1992, 266, 181-188. https://doi.org/10.1016/0027-5107(92)90185-5
  11. LaLonde, R. T.; Bu, L.; Henwood, A.; Fiumano, J.; Zhang, L.Chem. Res. Toxicol. 1997, 10, 1427-1436. https://doi.org/10.1021/tx9701283
  12. LaLonde, R. T.; Cook, G. P.; Perakyla, H.; Bu, L. Chem. Res.Toxicol. 1991, 4, 540. https://doi.org/10.1021/tx00023a009
  13. LaLonde, R. T.; Cook, G. P.; Perakyla, H.; Dence, C. W. Chem.Res. Toxicol. 1991, 4, 35-40. https://doi.org/10.1021/tx00019a005
  14. LaLonde, R. T.; Cook, G. P.; Perakyla, H.; Dence, C. W.; Babish,J. G. Environ. Mol. Mut. 1991, 17, 40. https://doi.org/10.1002/em.2850170107
  15. LaLonde, R. T.; Leo, H. Chem. Res. Toxicol. 1994, 7, 779-783. https://doi.org/10.1021/tx00042a010
  16. LaLonde, R. T.; Leo, H.; Perakyla, H.; Dence, C. W.; Farrell, R. P.Chem. Res. Toxicol. 1992, 5, 392-400. https://doi.org/10.1021/tx00027a012
  17. LaLonde, R. T.; Xie, S.; Bu, L. Environmental and MolcularMutagenesis 1993, 22, 181-187. https://doi.org/10.1002/em.2850220311
  18. Ishiguro, Y.; LaLonde, R. T.; Dence, C. W. Environ. Tox. andChem. 1987, 6, 935-946. https://doi.org/10.1002/etc.5620061205
  19. Ishiguro, Y.; Santononato, J.; Neal, M. W. Environ. Mol. Mut.1998, 11, 225-234.
  20. Kronberg, L.; Christman, R. F.; Singh, R.; Ball, L. M. Environ.Sci. Technol. 1991, 25, 99-104. https://doi.org/10.1021/es00013a009
  21. Kronberg, L.; Franzen, R. Environ. Sci. Technol. 1993, 27, 1811-1818. https://doi.org/10.1021/es00046a008
  22. Meier, J. R.; Knohl, R. B.; Coleman, W. E.; Ringhand, H. P.;Munch, J. W.; Kaylor, W. H.; Streicher, R. P.; Kopfler, F. C. Mutat.Res. 1987, 189, 363-373. https://doi.org/10.1016/0165-1218(87)90044-9
  23. Cho, S. J. Bull. Korean Chem. Soc. 2002, 23, 929-930. https://doi.org/10.5012/bkcs.2002.23.7.929

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