1: Mutat Res 1996 Jun 12;353(1-2):151-76
Development and validation of alternative metabolic systems for mutagenicity
testing in short-term assays.
Rueff J, Chiapella C, Chipman JK, Darroudi F, Silva ID, Duverger-van Bogaert
M, Fonti E, Glatt HR, Isern P, Laires A, Leonard A, Llagostera M, Mossesso
P, Natarajan AT, Palitti F, Rodrigues AS, Schinoppi A, Turchi G, Werle-Schneider
G
Department of Genetics and Microbiology, Autonomous University of Barcelona,
Bellaterra, Spain.
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.
Publication Types:
Review
Review, tutorial
PMID: 8692190, UI: 96288491