Mutagenicity of Closely Related Carcinogenic and Noncarcinogenic Compounds Using Various Metabolizing Systems and Target Cells
A total of 49 heteropolycyclic compounds belonging to structurally homogenous series was investigated for bacterial mutagenicity in the Ames test. The same batches of compounds were tested for carcinogenicity by injection into subcutaneous tissue of mice? 22 test compounds were carcinogenic, some strongly, others weakly. With the exception of one weak carcinogen, all these compounds were mutagenic. However, 15 of 27 noncarcinogens (56%) were also mutagenic. Moreover, noncarcinogenic, weakly carcinogenic, and strongly carcinogenic mutagens showed very similar mutagenic potencies.
To investigate the reasons for the many apparently false positives in the Ames test and for the complete lack of quantitative correlation, two groups of isomers were selected for further investigation. The first group of isomers consisted of the noncarcinogenic nonmutagen 2-fluoro-7-methyl-6H-benzothiopyrano-[4,3-b]quinoline (2-F-MBTQ), the noncarcinogenic mutagen 3-F-MBTQ, and the carcinogenic mutagen 4-F-MBTQ. The second group of isomers consisted of 7-methylbenzo(c)acridine and 12-methylbenzo-(a)acridine. Both were mutagenic, but whereas 7-methylbenzo(c)-acridine produced tumors essentially in all (522 of 523) animals surviving the minimal latency time of the experiment, no indication of carcinogenicity was found with 12-methylbenzo (a) acridine, although it was tested in many experiments using various strains and various routes of application with totally 554 animals
Modifications of the mammalian activating system in the mutagenicity test, such as the use of tissue preparations from mice treated with enzyme inducers, or the addition of cofactors for conjugating, potentially inactivating enzymes, had very similar effects on the mutagenicity of carcinogenic and noncarcinogenic isomers. Carcinogenic and noncarcinogenic isomers also did not differ in their enzyme-inducing ability. All five MBTQs and methy1-benzoacridines were mutagenic to mammalian (Balb 3T3) cells. In these cells carcinogens were more potent mutagens than the noncarcinogenic isomers, but the quantitative difference in mutagenicity was much smaller than the minimal estimate of the difference in carcinogenicity.
The elucidation of the reasons for such discrepancies is important for the interpretation of data obtained in short-term tests for carcinogenicity.
KeywordsGlutathione NADPH Fluorine Indole Epoxide
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