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 dimethylnitrosamine.
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 methyltransferase 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.
D000478:Alkylation; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
D004247:DNA; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004128:Dimethylnitrosamine; D013936:Thymidine