The bacterial mutagenicity of synthetic all-trans fecapentaene-12 changes when assayed under anaerobic conditions

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Abstract
Fecapentaenes are potent mutagens produced in the anaerobic environment of the human colon. The aim of this study was to determine the effect of anaerobic conditions on the bacterial mutagenicity of all-trans fecapentaene-12, a synthetic fecapen-taene. Fecapentaene-12 was tested aerobkally and anaer-obkaUy at doses from 0.25 to 4 μg/plate in agar-overlay assays with Salmonella typhimurium TA98 and TA100 and Escherichia coli WP2urnA(pKM101), and 0.01 to 2 μg/ml in fluctuation test with TA100. In agar-overlay tests, fecapentaene-12 was less mutagenic to the frameshift mutant TA98 under aerobic conditions than under anaerobic conditions (average slopes of 3.8 and 31.6 revertants/μg respectively). Aerobic assays using TA100 and E.coli WP2uvrA-(pKM101) gave respective slopes of 62.9 and 167.6. Anaerobic assays with these base-substitution mutants gave negative results under conditions in which positive controls were mutagenic. However, the numbers of spontaneous revertants in these anaerobic assays were substantially lower than normal. Microtitre fluctuation tests, known to perform equally well under both aerobic and anaerobic conditions, were conducted with TA100 to confirm that the activity of fecapentaene-12 as a base-substitution mutagen was attenuated under anaerobic conditions. Replicate aerobic assays gave an average slope (revertants/well/μg) of 0.41, compared with 0.056 for anaerobic assays—a > 7-fold difference. There was no significant difference in slope between aerobic and anaerobic positive controls. Thus, fecapentaene-12 may have two distinct modes of action, acting as a base-substitution mutagen and as a frameshift mutagen. Anaerobic conditions suppress the base-substitution activity but not the frameshift activity. These findings suggest that reactive but labile compounds such as fecapentaenes formed in the faecal stream are unreactive in the anaerobic environment of the lumen of the large bowel but could become reactive if they reached the oxygenated intestinal mucosa where expression of their genotoxicity could initiate neoplasia.