Persistence of O6-ethylguanine in rat-brain DNA: correlation with nervous system-specific carcinogenesis by ethylnitrosourea

Abstract

The nervous system specificity of the carcinogenic effect of N-ethyl-N-nitrosourea in rats at the perinatal age is of particular interest because the formation of the ultimate reactant, an electrophilic ethyl cation, occurs nonenzymatically and, hence, is not tissue specific. Indeed, similar initial degrees of DNA ethylation were found in the DNA of target (brain) and nontarget tissue (liver), in terms of the molar fractions of O6-ethylguanine, N7-ethylguanine, and N3-ethyladenine 1 hr after a pulse of [1-(14)C]ethylnitrosourea. However, over a 240-hr period of observation, the elimination rate from DNA of O6-ethylguanine (a modified base likely to cause anomalous base pairing during DNA replication) was strikingly slower in brain (half-life, about 220 hr) as compared to liver (about 30 hr), and also much slower than the elimination rates from brain DNA of N7-ethylguanine (about 90 hr) and N3-ethyladenine (about 16 hr). The data suggest that the rate of elimination from DNA of O6-ethylguanine may be an important factor (with the requirement for DNA replication of the target cell) in neoplastic transformation by ethylnitrosourea.