The mutagenicity, metabolism,
DNA adduction and induction of unscheduled
DNA synthesis (UDS) of
1-nitropyrene and
1,8-dinitropyrene were investigated in the human
hepatoma cell line HepG2. Previous results had demonstrated that
1-nitropyrene was both mutagenic at the
hgprt locus and induced UDS in these cells. In the present study, we find that the dinitropyrenes, although highly mutagenic in Salmonella typhimurium, are not mutagenic and do not induce UDS in the HepG2. Although the rate of
1,8-dinitropyrene nitroreduction was less than that of
1-nitropyrene nitroreduction, this did not explain the lack of mutagenicity and UDS induction by the dinitropyrenes. Therefore, it is proposed that the
arylhydroxylamine O-esterificase is not expressed in these cells. Since
cytochrome P450-mediated C-oxidation is the predominant metabolic pathway in vivo, we sought to determine if an increase in the ratio of
cytochrome P450-mediated C-oxidation over nitroreduction would result in increased or decreased
DNA adducts in the HepG2. The administration of 2.5 microM
3-methylcholanthrene to the HepG2 increased the ratio of C-oxidation/nitroreduction from 2.8 +/- 1.9 to 50.4 +/- 46.1. This was accompanied by a decrease in the C8-guanyl adduct of
1-nitropyrene (via nitroreduction) from 18.7 +/- 7.0 to 4.8 +/- 1.7 fmoles/micrograms
DNA, without any further increase in other
1-nitropyrene DNA adducts. These results suggest that the
cytochrome P450-mediated metabolism of
1-nitropyrene to
epoxides,
phenols, and dihydrodiols is not an activation pathway in the HepG2 cells, and may explain the weak carcinogenicity of
1-nitropyrene in vivo, where
cytochrome P450-mediated C-oxidation predominates.