Induction of micronuclei in metabolically competent rat hepatoma cell lines by the promutagens 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclophosphamide.
The capability of two rat hepatoma cell lines, H4IIEC3/G- and 2sFou, to detect genotoxicity of xenobiotics, was evaluated in a micronucleus assay. In this system, the cells act as the activation source as well as the target cells for the DNA damage. The study was performed using 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclophosphamide, as pro-mutagens and mitomycin C as a direct acting mutagen. In both cell lines a significant micronucleus induction was observed after exposure to each test compound, starting from 25 nM for 7,12-dimethylbenz[a]anthracene, 8 microM for benzo[a]pyrene, 0.5 mM for cyclophosphamide and 0.4 microM for mitomycin C. A period of 24 h treatment and 48 h growth was sufficient for induction and expression of micronuclei. The two hepatoma lines behave in a similar way with regard to the pro-mutagen activation. The results obtained in this study with these differentiated hepatoma lines demonstrate that they are metabolically competent to activate the promutagens 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclophosphamide into their biologically active metabolites as measured by micronucleus induction in our experiments. However, the variable dose responses to 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene in some of the repeated experiments, suggest unstable activity of enzymes involved in polycyclic aromatic hydrocarbons metabolism in these cell lines.
Tafazoli
M
M
Laboratory for Anthropogenetics, Faculty of Sciences, Free University of Brussels.
Van Hummelen
P
P
Kiefer
F
F
Kirsch-Volders
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001711:Biotransformation; D003520:Cyclophosphamide / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D015162:Micronucleus Tests; D016685:Mitomycin / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity*; D011355:Prodrugs / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D009153:Mutagens; D011355:Prodrugs; D001564:Benzo(a)pyrene; D016685:Mitomycin; D015127:9,10-Dimethyl-1,2-benzanthracene; D003520:Cyclophosphamide