HUMAN CELL MUTAGENICITY OF MONONITROPYRENES AND DINITROPYRENES IN METABOLICALLY COMPETENT MCL-5 CELLS

Nitropyrenes are ubiquitous environmental pollutants that may pose a h uman health hazard because some are highly potent mutagens and carcino gens. The mutagenicity (trifluorothymidine resistance at the thymidine kinase locus) of 1-, 2-, and 4-nitropyrene (1-, 2-, and 4-NP), 1,3-, 1,6-, and 1,8-dinitropyrene (1,3-, 1,6-, and 1,8-DNP), and pyrene was assessed in a quantitative forward mutation assay using a metabolicall y competent line (MCL-5) of human B-lymphoblastoid cells. These cells contain endogenous cytochrome P450 activity (CYP1A1) and two plasmids that express cDNAs for four additional P450s (CYP1A2, CYP2A6, CYP2E1, CYP3A4) and microsomal epoxide hydrolase found in human liver. The maj or finding is that 2-NP and 1,3-DNP, both potent bacterial mutagens, w ere nonmutagenic in this assay. The following mutagenic potency series , expressed as the minimum detectable mutagen concentration (MDMC) in nmol/ml, was obtained: 1,6-DNP (0.8), 1,8-DNP (1.5), 4-NP (3.1), 1-NP (9.1), 2-NP (> 81), 1,3-DNP (> 86), pyrene (> 494). There was over an ii-fold difference between the most potent (1,6-DNP) and the least pot ent (1-NP) mutagen. 1,6-DNP was approximately twice as mutagenic as 1, 8-DNP, which was almost twice as mutagenic as 4-NP, which, in turn was nearly three times as potent as 1-NP. This is the first report on the testing of 2-NP and 4-NP for mutagenicity in mammalian cell cultures. The human cell mutagenicity of these compounds was discussed in terms of potency series of nitropyrenes obtained from animal carcinogenicit y experiments and other mammalian cell mutagenicity assays.