Carcinogenesis and aging. II. Modifying effect of aging on metabolism of methyl(acetoxymethyl)nitrosamine and its interaction with DNA of various tissues in rats.

Young (3 month-old) and old (14 month-old) female outbred rats received a single i.p. dose (13 mg/kg) of N-[14C]methyl-Nacetoxymethylnitrosamine [( 14C]DMN-OAc), which, under these conditions, selectively induces intestinal tumours. Complete DMN-OAc breakdown occurred within 30 min in both young and old rats but exhalation of 14CO2 continued for over 1 h in young rats and over 3 h in old rats. The highest level of methylation in both young and old rats was found in the DNA of epithelial cells of the colon and in other adjacent abdominal organs (liver and uterus). The initial capacity for excision of the O6-methylguanine from liver DNA was greater in young animals, but further this DNA adduct was repaired more efficiently by the liver of old rats. In the DNA of ileal and colonic enterocytes, O6-methylguanine excision was higher in young than in old animals. The DNA tertiary structure, measured by the sedimentation pattern of nucleoids in neutral sucrose gradient, was damaged in old rats, and, to a lesser extent, in young rats. The non-uniform pattern of DNA damage in young and old animals may be associated with differing carcinogenic effects of DMN-OAc in rats of different ages, a hypothesis which is currently under test.