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Determinants of a genotoxic effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human diploid fibroblasts

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Summary

The induction of micronuclei was studied in human diploid fibroblasts incubated in the presence of the tobacco-specific nitrosamine NNK. We used four fibroblast strains having a high capacity of 06-alkylguanine DNA alkyltransferase (13.0–23.3 pmol 06-methylguanine repaired per 8 × 106 cells) and four strains that showed no detectable repair capacity. Incubation with NNK doubled the frequency of micronuclei in repair-deficient cells but failed to evoke any effect in the proficient cell strains. Control experiments were performed with the direct methylating agent MNNG and in the presence of inhibitors of either metabolic activation or alkyltransferase. The results showed that the genotoxicity of NNK is dependent on the relationship between its metabolic activation and the constitutive DNA repair. This supports earlier findings that low constitutive levels of 06-alkylguanine DNA alkyltransferase may increase susceptibility to lung cancer after exposure to DNA methylating agents.

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Abbreviations

NNK:

4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone

MNNG:

N-methyl-N′-nitro-N-nitrosoguanidin

MN:

micronuclei

O6-AT:

O6-alkylguanine-DNA-alkyl-transferase

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Author notes

  1. H. W. Rüdiger

    Present address: Arbeitsgruppe Toxikogenetik Ordinariat für Arbeitsmedizin, Universität Hamburg Adolph-Schönfelder, Strasse 5, W-2000, Hamburg 76, Germany

Authors and Affiliations

  1. Arbeitsgruppe Toxikogenetik, Ordinariat für Arbeitsmedizin, Universität Hamburg, Germany

    C. Pohlmann, F. Koops, J. Berg, O. Holz, U. Ehlert &  H. W. Rüdiger

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  1. C. Pohlmann
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  2. F. Koops
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  3. J. Berg
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  4. O. Holz
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  5. U. Ehlert
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  6. H. W. Rüdiger
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This work is part of a thesis for a medical doctorate of CP

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Pohlmann, C., Koops, F., Berg, J. et al. Determinants of a genotoxic effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human diploid fibroblasts. Clin Investig 70, 295–298 (1992). https://doi.org/10.1007/BF00184665

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  • DOI: https://doi.org/10.1007/BF00184665

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