Co-mutagenicity of coumarin (1,2-benzopyrone) with aflatoxin B₁ and human liver S9 in mammalian cells

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 B₁ with human liver S9 bioactivation in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay. Coumarin in the absence of aflatoxin B₁ was not mutagenic or cytotoxic up to 500 μM. When included with either 1 or 10 μM aflatoxin B₁, coumarin produced a dose-dependent increase in mutant frequency and cytotoxicity. At concentrations greater than 50 μM, coumarin stimulated human liver S9 bioactivation of aflatoxin B₁ to the mutagenic 8,9-epoxide. This increase was 12- and fivefold at 500 μM coumarin with 1 and 10 μM aflatoxin B₁, respectively, compared with incubations with aflatoxin B₁ alone. These findings differ from previous results with liver S9 from other species, and indicate that coumarin co-mutagenicity with aflatoxin B₁ and human liver S9 is through increased aflatoxin B₁ bioactivation. Copyright (C) 1999 Elsevier Science Ltd.