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Dosimetry of O6 in rat DNA after low-dose, chronic exposure to N-nitrosodimethylamine (NDMA). Implications for the mechanism of NDMA hepatocarcinogenesis
1Laboratory of Chemical Carcinogenesis, Institute of Biological Research and Biotechnology. National Hellenic Research Foundation, 48 Vassileos Constantinou Ave Athens 11635, Greece
2Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center Frederick, MD, USA
3To whom correspondence should be addressed
Groups of female Wistar Furth/NCr rats, aged 6 weeks or 7 months at the start of the experiment, were adminis tered drinking water containing N-nitrosodimethylamine (NDMA) for up to 28 days at concentrations in the range 0.2–2.64 p.p.m., resulting in daily intakes in the range 28–372 µg/kg/day at age 10 weeks. The levels of the premutagenic DNA adduct O6-menthylguanine (O6-meG in liver and blood leukocyte DNA were measured at different times during this exposure as well as on the days immediately following cessation of exposure. The adduct was found to accumulate rapidly in both tissues, reaching within 2–7 days steady states in the range 0.08–0.45 µmnol/molG, similar in young and adult animals. Accumulation of O6-meG in blood leukocytes was 
30% lower than in the liver. Following cessation of NDMA treatment, adducts were lost rapidly from the DNA of both tissues, with an apparent t1/2 of 19–23 h for the liver and 30–35 h for blood leukocytes. No change in liver O6-alkyltrans ferase (AGT) took place throughout this treatment. The steady-state adduct levels were approximately linearly related to NDMA dose-rate, except that a clear break (corresponding to a 2.6-fold lower slope) was observed at dose rates>0.4 p.p.m. (56 µg/kg/day). This dose-response relationship is in contrast to the sharp increase in the liver tumour induction in rats chronically treated with similar concentrations of NDMA reported by Peto et al. (Cancer Res., 51, 6415–6451) and suggests that accumulation of O6-meG cannot by itself account for the hepatocarcinogenic efficacy of NDMA in the rat. Following i.g. administration of single doses of NDMA in a range approximately corresponding to the daily intake during the above mentioned chronic exposure study (25, 50 or 100 µg/kg), repair of O6-meG followed sharply biphasic kinetics in both liver and blood leukocytes. In the liver, an initial rapid phase (t1/2 1.5–1.7 h) was followed by much slower repair (t1/2 20.7–24.9 h) despite the absence of any change in AGT. Extrapolation of the two segments of the repair kinetics plots back to 0 time suggests that 52–61% of the adducts originally formed in the liver and 33–35% of those formed in blood leukocytes belonged to the rapidly repaired category. The observation of biphasic repair under conditions of full AGT activity implies the existence of adduct populations with different susceptibility to repair possibly reflecting adducts in different cell types or in different chromatin regions. The rate of loss of O6-meG from DNA following cessation of chronic treatment was similar to that of the slowly repaired category of adducts, confirming that only adducts of this category accumulate during chronic exposure.
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