Nitropyrenes are inducers of polyoma viral DNA synthesis

Abstract

The biological activity of a series of nitopyrenes was assayed by measuring their ability to induce the asynchronous replication of viral DNA in rat fibroblasts transformed by a st-a mutant of polyoma virus. Concentrations of 10–30 μg/ml of 1-nitropyrene (1-NP) induced viral replications, and this effect was enhanced by addition of rat-liver S9 microsomal fraction (300 μ/ml) to the culture medium. The response was less than that obtained with 0.1 μg/ml of the activated metabolite of benzo[ a]pyrene (BP), BP trans-7,8-dihydrodiol-9,10 epoxide (anti) (BPDE). A series of di-, tri-, and tetra-nitropyrenes were also found to induce polyoma DNA replicatin, in the absence of exogenous microsomal activation, displaying strongly positive effects at 0.5–2.0 μg/ml. Dose-response curves with 1,6-dinitropyrene (1,6-DNP) from 0.01 to 0.5 μg/ml inidcated that this compound was approximately equipotent with BPDE for induction of polyoma DNA synthesis. Studies of drug metabolism, DNA binding and DNA adduct formation indicate that 1,6-DNP is metabolized in this cell line, binds to DNA, and forms stable adducts. The level of DNA modifications seen with, 1,6-DNP is higher than that observed under comparable conditions with an equivalent dose of BPDE. These findings provide additional evidence that the nitropyrene class of compounds can exert biological effects in mammalian cells, and that the dinitropyrenes are more potent than 1-NP.