Journal Article

Heterocyclic aromatic amines induce DNA strand breaks and cell transformation

Wolfgang Pfau, Francis L. Martin, Kathleen J. Cole, Stanley Venitt, David H. Phillips, Philip L. Grover and Hans Marquardt

in Carcinogenesis

Volume 20, issue 4, pages 545-551
Published in print April 1999 | ISSN: 0143-3334
Published online April 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.4.545
Heterocyclic aromatic amines induce DNA strand breaks and cell transformation

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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 (AαC), 100 μM 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) 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 AαC, 2.9 revs/ng with MeAαC 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 > MeAαC > PhIP > AαC. 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, MeAαC and AαC, 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.

Keywords: AAF, 2-acetylaminofluorene; AαC, 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; MeAαC, 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.

Journal Article.  5143 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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