Co-mutagenicity of Coumarin (1,2-benzopyrone) with Aflatoxin B 1 and Human Liver S9 in Mammalian Cells

Abstract

Coumarin (1,2-benzopyrone), a natural dietary constituent and drug currently under evaluation for treatment of certain cancers and lymphedema, reduces polycyclic aromatic hydrocarbon-induced neoplasms in rodents. Because most rodents metabolize coumarin through 3,4-epoxidation, whereas 7-hydroxylation predominates in humans, their suitability as a model for coumarin effects in humans has been questioned. We examined coumarin chemoprotection against the promutagen and dietary contaminant aflatoxin B 1 with human liver S9 bioactivation in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay. Coumarin in the absence of aflatoxin B 1 was not mutagenic or cytotoxic up to 500 μ m. When included with either 1 or 10 μ m aflatoxin B 1, coumarin produced a dose-dependent increase in mutant frequency and cytotoxicity. At concentrations greater than 50 μ m, coumarin stimulated human liver S9 bioactivation of aflatoxin B 1 to the mutagenic 8,9-epoxide. This increase was 12- and fivefold at 500 μ m coumarin with 1 and 10 μ m aflatoxin B 1, respectively, compared with incubations with aflatoxin B 1 alone. These findings differ from previous results with liver S9 from other species, and indicate that coumarin co-mutagenicity with aflatoxin B 1 and human liver S9 is through increased aflatoxin B 1 bioactivation.