Development and validation of alternative metabolic systems for mutagenicity testing in short-term assays

J. Rueff, C. Chiapella, J. K. Chipman, F. Darroudi, I. Duarte Silva, M. Duverger-Van Bogaert, E. Fonti, H. R. Glatt, P. Isern, A. Laires, A. Léonard, M. Llagostera, P. Mossesso, A. T. Natarajan, F. Palitti, A. S. Rodrigues, A. Schinoppi, G. Turchi, G. Werle-Schneider

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Abstract

We present here the results obtained within the framework of an EU funded project aimed to develop and validate alternative metabolic activating systems to be used in short term mutagenicity assays, in order to reduce the use of laboratory animals for toxicology testing. The activating systems studied were established cell lines (Hep G2, CHEL), genetically engineered V79 cell lines expressing specific rat cytochromes P450, erythrocyte-derived systems, CYP-mimetic chemical systems and plant homogenates. The metabolically competent cell lines were used as indicator cells for genotoxic effects as well as for the preparation of external activating systems using other indicator cells. The following endpoints were used: micronuclei, chromosomal aberrations and sister chromatid exchanges, mutations at the hprt locus, gene mutations in bacteria (Ames test), unscheduled DNA synthesis and DNA breaks detected in the comet assay. All metabolic systems employed activated some promutagens. With some of them, promutagens belonging to many different classes of chemicals were activated to genotoxicants, including carcinogens negative in liver S9-mediated assays. In other cases, the use of the new activating systems allowed the detection of mutagens at much lower substrate concentrations than in liver S9-mediated assays. Therefore, the alternative metabolizing systems, which do not require the use of laboratory animals, have a substantial potential in in vitro toxicology, in the basic genotoxicity testing as well as in the elucidation of activation mechanisms. However, since the data basis is much smaller for the new systems than for the activating systems produced from subcellular liver preparations, the overlapping use of both systems is recommended for the present and near future. For example, liver S9 preparations may be used with some indicator systems (e.g., bacterial mutagenicity), and metabolically competent mammalian cell lines may be used with other indicator systems (e.g., a cytogenetic endpoint) in a battery of basic tests.
Original languageEnglish
Pages (from-to)151-176
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume353
DOIs
Publication statusPublished - 12 Jun 1996

Keywords

  • Ames test
  • Bioactivation of mutagen
  • CHEL cell
  • Cell survival
  • Chromosome aberration
  • Cytochrome P450
  • Erythrocyte
  • Gene mutation assay
  • Human Hep G2 cell
  • Micronuclei
  • Peroxidase activity
  • Plant activation
  • Sister chromatid exchange
  • V79-derived Chinese hamster cell

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    Rueff, J., Chiapella, C., Chipman, J. K., Darroudi, F., Duarte Silva, I., Duverger-Van Bogaert, M., Fonti, E., Glatt, H. R., Isern, P., Laires, A., Léonard, A., Llagostera, M., Mossesso, P., Natarajan, A. T., Palitti, F., Rodrigues, A. S., Schinoppi, A., Turchi, G., & Werle-Schneider, G. (1996). Development and validation of alternative metabolic systems for mutagenicity testing in short-term assays. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 353, 151-176. https://doi.org/10.1016/0027-5107(95)00246-4