Metronidazole and Misonidazole: Absence of Cytogenetic Effects in a Euoxic Bacterial and a Mammalian Cell System In Vitro

  • J. R. Dunlop
  • J. S. Mahood
  • R. L. Willson
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 42)


The drug metronidazole (Flagyl) has been widely used for many years in the treatment of trichomoniasis amoebiasis and giardiasis and is currently proving of considerable benefit in the treatment of anaerobic infections generally (1). Along with a related compound misonidazole (Ro-07-0582) it is also presently undergoing trials as an adjunct in cancer radiotherapy (2–4). Concern about its use has been expressed, however, particularly in the United States because of the reports of its mutagenic and carcinogenic activity in bacterial and animal systems (5–12). The relevance of these reports to the human situation has been the subject of much discussion (1,13). An increase in chromosome aberrations above untreated controls has been found in patients undergoing treatment for Crohn’s disease (14) although a similar study in patients being treated for Trichomonas vaginalis no increase was detectable (15). Like metronidazole, misonidazole has also been shown to be active in bacterial and mammalian systems in vitro (16,17).


Chromosome Aberration Sister Chromatid Exchange Hypoxic Cell Anaerobic Infection Cytogenetic Effect 
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  1. 1.
    E. J. Baines, Metronidazole, Excerpta Medica, S.M. Finegold, ed. p.61 and refs. cited. (1977).Google Scholar
  2. 2.
    C. R. Wiltshire, P. Workman, J. V. Watson and N. M. Bleehen, Clinical studies with misonidazole, Br. J. Cancer 37 Suppl. Ill, 286 (1978).Google Scholar
  3. 3.
    R.C. Urtasun, J.D. Chapman, P. Band, H. Rabin, C. Fryer and J. Sturmwind, Phase 1 Study of high-dose metronidazole on in vivo and in vitro specific radiosensitizer of hypoxic cells. Radiology 117: 127 (1975).Google Scholar
  4. 4.
    S. Dische and M.I. Saunders, Clinical experience with misonidazole. Br.J. Cancer 37 Suppl.Ill, 311 (1978).Google Scholar
  5. 5.
    C.E. Voogd, J.J. Van Der Stel and J.J.J.A.A. Jacobs, The mutagenic action of nitroimidazoles, I. Metronidazole, nimorazole, dimetridazole and ronidazole, Mutation Res. 26: 483 (1974).PubMedCrossRefGoogle Scholar
  6. 6.
    M.S. Legator, Т.Н. Connor and M. Stoeckel, Detection of mutagenic activity of metronidazole and niridazole in body fluids of humans and mice, Science 188: 1118 (1975).PubMedCrossRefGoogle Scholar
  7. 7.
    W.T. Speck, A.B. Stein and H.S. Rosenkranz, Mutagenicity of metronidazole: presence of several active metabolites in human urine, J. Natl, Cancer Inst. 56:283 (1976).Google Scholar
  8. 8a.
    H.S. Rosenkranz and W.T. Speck, Mutagenicity of metronidazole: activation by mammalian microsomes, Biochem.Biophys.Res. Commun. 66: 520 (1975).Google Scholar
  9. 8b.
    b D.G. Lindmark and M. Muller, Antitrichomonal action, mutagenicity and reduction of nitroimidazoles, Antimicrobiol Agents Chemotherapy 10:Google Scholar
  10. 9.
    J.B. Chin, D.M.K. Sheinin and A.M. Rauth, Screening for the Mutagenicity of Nitro group containing Hypoxic Cell Radio- sensitizers using Salmonella typhimurium strains TA.100 and TA.98. Mutation Res. 58: 1 (1978).PubMedCrossRefGoogle Scholar
  11. 10.
    Tong-Man Ong, B. Slade and F.J. de Serres, Mutagenicity and mutagenic specificity of metronidazole and niridazole in Neurospora. Crassa. J. Toxicol.Environ.Health 4: 815 (1978).PubMedCrossRefGoogle Scholar
  12. 11.
    M. Rustia and P. Shubik, Induction of lung tumors and malignant lymphomas in mice by metronidazole. J. Natl.Cancer Inst. 48: 721 (1972).PubMedGoogle Scholar
  13. 12.
    M. Rustia and P. Shubik, Experimental induction of hepatomas, mammary tumors and other tumors with metronidazole in non- inbred Sas:MRC (WI) BR rats. J. Natl. Cancer Inst. 63: 863 (1979).PubMedGoogle Scholar
  14. 13.
    C.M. Beard, K.L. Noller, W.M. O’Fallon, L.T. Kurland and M.B. Dockerty, Lack of evidence for cancer due to use of metronidazole. New Eng. J. Med. 301: 519 (1979).PubMedCrossRefGoogle Scholar
  15. 14.
    F. Mitelman, B. Hartley-Asp and B. Ursing, Chromosome aberrations and metronidazole. Lancet October 9th p. 802 (1976).Google Scholar
  16. 15.
    B. Hartley-Asp, Mutagenicity of metronidazole. Lancet February 3rd, p. 275 (1979).Google Scholar
  17. 16.
    W.D. Rupp, Z. Mroczkowski and K.C. Agrawal, Hypoxic radio- sensitizers: prospects for effective compounds with fewer toxic side effects. Br. J. Cancer 37 Suppl.III, 60 (1978).Google Scholar
  18. 17.
    E.J. Hall, R. Miller, M. Astor and R. Rini, The nitroimidazoles as radiosensitizers and cytotoxic agents. Br. J. Cancer 37 Suppl. Ill, 120 (1978).Google Scholar
  19. 18.
    M.H.L. Green and W.J. Muriel, Mutagen testing with Trp+ reversion in Escherichia coli. Mutation Res. 38: 3 (1976).PubMedCrossRefGoogle Scholar
  20. 19.
    P. Perry and S. Wolff, New Giemsa method for the differential staining of sister chromatids. Nature 251: 156 (1974).PubMedCrossRefGoogle Scholar
  21. 20.
    P. Perry and H.J. Evans, Cytological detection of mutagen- carcinogen exposure by sister chromatid exchange. Nature 258: 121 (1975).PubMedCrossRefGoogle Scholar
  22. 21.
    C.M. Woolf, Principles of Biometry. D. Van Nostrand Co. Ltd. pp. 106 and 116.Google Scholar
  23. 22.
    R.G. Bost, Metronidazole. S.M. Finegold ed. Excerpta Medica p.126, (1977).Google Scholar
  24. 23.
    R.J. Trzos, G.L. Petzold, M.N. Brunden and J.R. Stenberg, The evaluation of sixteen carcinogens in the rat using the micro-nucleus test. Mutation Res. 58: 79 (1978).PubMedCrossRefGoogle Scholar
  25. 24.
    S.H. Basaga, J.R. Dunlop, A.J.F. Searle and R.L. Willson, Metronidazole (Flagyl) and misonidazole (Ro-07-0582): reduction by facultative anaerobes and cytotoxic action on hypoxic bacteria and mammalian cells in vivo. Br.J.Cancer 37, Suppl.III, 132. (1978).Google Scholar
  26. 25.
    A.J.F. Searle and R.L. Willson, Metronidazole (Flagyl) degradation by the intestinal flora. Xenobiotica 6: 457 (1976).PubMedCrossRefGoogle Scholar
  27. 26.
    H.N. Prince, E. Grunberg, E. Titsworth and W.F. Delorenzo, Effects of 1- (2-nitro-l-imidazolyl) -3-methoxy-2-propanol and 2-methyl-5-nitroimidazole-l-ethanol against anaerobic and aerobic bacteria and protozoa. Applied Microbiol. 18: 728 (1969).Google Scholar
  28. 27.
    R.L. Willson and A.J.F. Searle, Metronidazole (Flagyl): iron catalysed reaction with sulphydryl groups and tumour radio- sensitisation. Nature 255: 498 (1975).PubMedCrossRefGoogle Scholar
  29. 28.
    D. Bahnemann, H. Basaga, J.R. Lunlop, A.J.F. Searle and R.L. Willson, Metronidazole (Flagyl) misonidazole (Ro-07- 0582), iron, zinc and sulphur compounds in cancer therapy. Br. J. Cancer 37:Suppl.III 16 (1978).Google Scholar
  30. 29.
    R.L. Willson, Metronidazole (Flagyl) in Cancer Radiology in: “Metronidazole”, S.M. Finegold ed. Excerpta Medica p.147 (1977).Google Scholar
  31. 30.
    E.J. Clarke, K.H. Golding and P. Wardman, Anaerobic production of nitroimidazoles by reduced flavin monocleotide and by xanthine oxidase. Biochem. Pharmacol. In press.Google Scholar
  32. 31.
    J.S. Mahood and R.L. Willson, Cytotoxicity of metronidazole (Flagyl) and misonidazole (Ro-07-0582) enhancement by lactate. Br. J. Cancer. Submitted.Google Scholar
  33. 32.
    P. Wardman, The use of nitroaromatic compounds as hypoxic cell radiosensitizers. Curr.Top.Radiat.Res.Quat. 11: 347 (1977).Google Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • J. R. Dunlop
    • 1
  • J. S. Mahood
    • 1
  • R. L. Willson
    • 1
  1. 1.Biochemistry DepartmentBrunel UniversityUxbridge, MiddlesexUK

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