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Dose Response for DNA Alkylation, [³H]Thymidine Uptake into DNA, and O⁶-Methylguanine-DNA Methyltransferase Activity in Hepatocytes of Rats and Mice Continuously Exposed to Dimethylnitrosamine¹

Department of Pathology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

The objectives of these experiments were to determine N-7-methylguanine (m⁷Gua) and O⁶-methylguanine (O⁶mGua) concentrations in DNA, [³H]thymidine uptake into DNA, and O⁶mGua-DNA methyltransferase activity in hepatocytes of F-344 rats and C3H and C57BL mice exposed to 0, 10, 30, or 100 ppm dimethylnitrosamine (DMN) ad libitum in their drinking water for 16 days. The 100-ppm DMN exposure regimen was lethal to the C3H mice. Using water consumption and body weight to surface area conversions, these exposures averaged 5, 13, and 27 mg/sq m/day for F-344 rats, 6, 16, and 31 mg/sq m/day for C57BL mice, and 6 and 16 mg/sq m/day for C3H mice. Over a 5-fold range of DMN exposure, m⁷Gua concentrations in DNA of rat hepatocytes increased 9-fold, while O⁶mGua concentrations increased only 3-fold. In contrast, while m⁷Gua increased 4-fold, O⁶mGua increased 14-fold in both strains of mice. O⁶mGua-DNA methyltransferase activity in rat hepatocytes was increased to 150% that of control values at the low exposure, and to 200% at the intermediate and high exposures of DMN. Methyltransferase activity in both strains of mice decreased with increasing exposure to DMN, such that C3H hepatocytes had only 59 and 20% as much activity as controls, while C57BL hepatocytes had 68, 38, and 14% as much methytransferase activity. Relative to controls, the only significant increase in [³H]thymidine uptake into DNA of hepatocytes occurred at 30 ppm DMN in C3H mice. We conclude that under conditions of DMN exposure leading to comparable m⁷Gua and O⁶mGua concentrations in DNA, O⁶mGua-DNA methyltransferase activity is enhanced in F-344 rats, but partially depleted in C57BL and C3H mice.

¹ Presented at the 74th Annual Meeting of the American Association for Cancer Research, San Diego, Calif., May 25 to 28, 1983 (19).

² Present address: Southern Research Institute, 2000 Ninth Ave. South, Birmingham, Ala. 35205.

³ To whom requests for reprints should be addressed, at P.O. Box 12137, Research Triangle Park, N. C. 27709.

Received 7/ 5/83. Accepted 10/ 7/83.

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