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Carcinogenesis, Vol. 20, No. 4, 545-551, April 1999
© 1999 Oxford University Press

Heterocyclic aromatic amines induce DNA strand breaks and cell transformation

Wolfgang Pfau2, Francis L. Martin1, Kathleen J. Cole1, Stanley Venitt1, David H. Phillips1, Philip L. Grover1 and Hans Marquardt

Fraunhofer Society, Department of Toxicology and Environmental Medicine and Department of Toxicology, Hamburg University Medical School, D-20146 Hamburg, Germany and
1 Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey SM2 5NG, UK

Heterocyclic aromatic amines (HAAs), formed during the cooking of foods, are known to induce tumours in rodent bioassays and may thus contribute to human cancer risk. We tested six HAAs in a morphological transformation assay and in three in vitro genotoxicity assays. The morphological transforming abilities of HAAs were tested, in the presence of rat-liver S9, in the C3H/M2 fibroblast cell line. Concentration levels of 50 µM 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 100 µM 2-amino-3,4,8-trimethylimidazo-[4,5-f]quinoxaline (4,8-DiMeIQx), 50 µM 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 100 µM 2-amino-9H-pyrido[2,3-b]indole (A{alpha}C), 100 µM 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA{alpha}C) and 15 µM 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced maximum transformation potencies of 5.5, 6.6, 6.3, 5.2, 7.3 and 9.2 transformed foci per 104 surviving cells, respectively. Bacterial mutagenic activity was determined in the presence of rat-liver S9 using the Salmonella typhimurium reverse-mutation assay employing strain YG1019. Mutagenic potencies of 3800 revertants (revs)/ng with 8-MeIQx, 2900 revs/ng with 4,8-DiMeIQx, 3480 revs/ng with IQ, 1.6 revs/ng with A{alpha}C, 2.9 revs/ng with MeA{alpha}C and 5 revs/ng with PhIP were observed. Clastogenic activity in vitro was analysed by the micronucleus assay in metabolically competent MCL-5 cells. Dose-dependent induction of micronuclei was observed for all HAAs tested with 1–5.4% of cells containing micronuclei at 10 ng/ml. Micronucleus induction was in the order 4,8-DiMeIQx > 8-MeIQx > IQ > MeA{alpha}C > PhIP > A{alpha}C. DNA strand-breaking activity in MCL-5 cells was measured by the alkaline single cell-gel (comet) assay. The lowest effect doses for significant increases (P <= 0.0007, Mann–Whitney test) in comet tail length (µm) were 45.5 µg/ml (200 µM) for PhIP, 90.9 µg/ml (410–510 µM) for 4,8-DiMeIQx, IQ, MeA{alpha}C and A{alpha}C, and 454.5 µg/ml (2130 µM) for 8-MeIQx. It is not yet clear which of these assays most accurately reflects the genotoxic potential to humans of compounds of this class of environmental carcinogens.

Abbreviations: AAF, 2-acetylaminofluorene; A{alpha}C, 2-amino-9H-pyrido-[2,3-b]indole; CA, chromosomal aberration; CHL, Chinese hamster lung; CHO, Chinese hamster ovary; 4,8-DiMeIQx, 2-amino-3,4,8-trimethylimidazo-[4,5-f]quinoxaline; DMSO, dimethyl sulphoxide; HAA, heterocyclic aromatic amine; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; MCA, 3-methylcholanthrene; MeA{alpha}C, 2-amino-3-methyl-9H-pyrido[2,3-b]indole; 8-MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; rev, revertant; SCE, sister chromatid exchange.

2 To whom correspondence should be addressed Email: pfau{at}uke.uni-hamburg.de


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