Mutagenicity of C 24H 14 PAH in human cells expressing CYP1A1

Abstract

Relatively little is known about the mutagenicity of C 24H 14 PAH, a diverse group of five- and six-ring PAH, some of which are present at trace levels in the environment. To better understand the mutagenicity of this class of compounds, 11 C 24H 14 PAH, including benzo[ a]perylene, benzo[ b]perylene, dibenzo[ a, e]fluoranthene, dibenzo[ a, f]fluoranthene, dibenzo[ j, l]fluoranthene, dibenzo[ a, h]pyrene, dibenzo[ a, i]pyrene, dibenzo[ e, l]pyrene, naphtho[1,2- b]fluoranthene, naphtho[2,3- a]pyrene, and naphtho[2,3- e]pyrene, were tested in a mutagenicity assay based on human h1A1v2 cells. h1A1v2 cells are a line of human B-lymphoblastoid cells that have been engineered to express cytochrome P4501A1 (CYP1A1), an enzyme capable of metabolizing promutagenic PAH. Mutagenicity was measured at the thymidine kinase ( tk) locus following a 72-h exposure period. Our results show that nine of the compounds were mutagenic. Benzo[ a]perylene, dibenzo[ a, e]fluoranthene, dibenzo[ a, i]pyrene, and naphtho[2,3- a]pyrene were the most potent mutagens, having minimum mutagenic concentrations (MMC) (i.e., the dose at which the induced response was twice that of the negative controls) in the 1–5 ng/ml range. Benzo[ b]perylene, dibenzo[ a, h]pyrene, dibenzo[ a, f]fluoranthene, and naphtho[2,3- e]pyrene were somewhat less potent mutagens, having MMC in the 10–30 ng/ml range. Dibenzo[ e, l]pyrene, which had an MMC of 280 ng/ml, was the least potent mutagen. Dibenzo[ j, l]fluoranthene and naphtho[1,2- b]fluoranthene were not mutagenic at the doses tested (1–3000 ng/ml). The most mutagenic compounds were also quite toxic. At the highest doses tested, benzo[ a]perylene, dibenzo[ a, e]fluoranthene, dibenzo[ a, i]pyrene, dibenzo[ a, h]pyrene, and dibenzo[ a, f]fluoranthene induced >60% killing, and naphtho[2,3- a]pyrene and naphtho[2,3- e]pyrene induced >50% killing. Benzo[ b]perylene, dibenzo[ e, l]pyrene, dibenzo[ j, l]fluoranthene, and naphtho[1,2- b]fluoranthene induced <50% killing at the highest doses tested. Comparing these results to a previous study in which nine other C 24H 14 PAH were tested for mutagenicity in this same assay, it was found that dibenzo[ a]pyrene isomers were generally more mutagenic than the other groups of C 24H 14 PAH tested. These observations are discussed with emphasis given to identifying C 24H 14 PAH that may be important environmental mutagens.