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Mutagenicity, Unscheduled DNA Synthesis, and Metabolism of 1-Nitropyrene in the Human Hepatoma Cell Line HepG2¹

Department of Environmental Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

The cell line HepG2 is derived from a well differentiated human hepatoblastoma, which retains many of the morphological characteristics of liver parenchymal cells. These cells at passages >95 were found to metabolically activate carcinogens to genotoxic metabolites. The addition of 6.8 µM 1-methyl-3-nitro-1-nitrosoguanidine, 5.3 µM 4-nitroquinoline-N-oxide, and 4-20.3 µM 1-nitropyrene resulted in the induction of mutations at the HGPRT locus as determined by 6-thioguanine resistance. This is the first description of the induction of mutations in these cells. Additionally, unscheduled DNA synthesis in the presence of 4 mM hydroxyurea was increased by 9% with 5.3 µM 4-nitroquinoline-N-oxide, 57% with 13.6 µM 1-methyl-3-nitro-1-nitrosoguanidine, and 300% with 8.2 µM 1-nitropyrene. High performance liquid chromatographic analysis of metabolites formed following incubation of HepG2 with either [³H]-1-nitropyrene or [¹⁴C]benzo(a)pyrene demonstrate the occurrence of arene oxidation as well as nitroreduction.

¹ Supported by the NIH, with Grant ES 03648 to P. C. H., Grant CA 32126 to G. D. M., and Grant ES 02827 to H. S. R.

² To whom requests for reprints should be addressed.

Received 12/ 1/86. Revised 3/10/87. Accepted 3/19/87.

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