3-amino-1-4-dimethyl-5h-pyrido(4-3-b)indole and Carcinoma--Hepatocellular

In order to study the mutagenic effects of heterocyclic aromatic amines (HAAs) in cells of human origin, five compounds, namely 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-3, 4-dimethyl-imidazo[4,5-f]quinoline (MeIQ), 2-amino-3, 8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), the pyridoimidazo derivative 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were tested in micronucleus (MN) assays with a human derived hepatoma (HepG2) cell line. All HAAs caused significant, dose-dependent effects. The activities of IQ, MeIQ, MeIQx and PhIP were similar (lowest effective concentrations 25-50 microM), whereas Trp-P-1 was effective at a dose of >/=2.1 microM. In addition, the HAAs were tested in MN assays with Chinese hamster ovary (CHO) cells and in Salmonella strain YG1024 using HepG2 cell homogenates as an activation mix. In the CHO experiments, positive results were obtained with Trp-P-1 and PhIP, whereas the other compounds were devoid of activity under all experimental conditions. The discrepancy in the responsivity of the two cell lines is probably due to differences in their acetylation capacity: enzyme measurements with 2-aminofluorene as a substrate revealed that the cytosolic acetyltransferase activity in the HepG2 cells is approximately 40-fold higher than that of the CHO cells. In the bacterial assays all five HAAs gave positive results but the ranking order was completely different from that seen in the HepG2/MN experiments (IQ > MeIQ > Trp-P-1 >/= MeIQx >> PhIP) and the mutagenic potencies of the various compounds varied over several orders of magnitude. The order obtained in bacterial tests with rat liver S9 mix was more or less identical to that seen in the tests with HepG2 cell homogenates but the concentrations of the amines required to give positive results were in general substantially lower (10(-5)-10(-1) microM). Overall, the results of the present study indicate that MN/HepG2 tests might reflect the mutagenic effects of HAAs more adequately than other in vitro mammalian cell systems due to the presence of enzymes involved in the metabolic conversion of the amines.

Topics: Amines; Animals; Arylamine N-Acetyltransferase; Carbolines; Carcinogens; Carcinoma, Hepatocellular; Cell Line; Cell Survival; CHO Cells; Cricetinae; Heterocyclic Compounds; Humans; Imidazoles; Liver Neoplasms; Mutagenicity Tests; Mutagens; Quinolines; Quinoxalines; Rats; Salmonella; Tumor Cells, Cultured

The effects of dietary bioantimutagens (compounds which have been shown to inhibit mutagenesis via interaction with DNA repair processes) on spontaneous and heterocyclic amine (HCA)-induced micronucleus (MN) frequencies were studied in metabolically competent human hepatoma (Hep-G2) cells. All the compounds tested (coumarin, vanillin, caffeine, tannic acid and cinnamaldehyde) caused a moderate increase of MN numbers in Hep-G2 cells at high concentrations (500 microg/ml); only tannic acid was also active at lower dose levels. In combination experiments with the HCA 2-amino-3-methylimidazo-[3,4-f]quinoline (IQ), post-treatment of the cells with bioantimutagens resulted in a pronounced (75-90%) decrease in MN. The most drastic effects were seen with vanillin, coumarin and caffeine which were active at concentrations < or = 5 microg/ml. Further experiments indicated that these compounds also attenuate the mutagenic effects of other HCAs (PhIP, MeIQ, MeIQx, Trp-P-1).

Topics: Acrolein; Amines; Antimutagenic Agents; Benzaldehydes; Caffeine; Carbolines; Carcinoma, Hepatocellular; Coumarins; DNA Repair; Heterocyclic Compounds; Humans; Hydrolyzable Tannins; Imidazoles; Micronucleus Tests; Mutagens; Quinolines; Tumor Cells, Cultured