Tissue-dependent enzyme-mediated repair or removal of O-ethyl pyrimidines and ethyl purines in carcinogen-treated rats.

Treatment of perinatal rats with N-ethyl-N-nitrosourea (EtNU) leads predominantly to brain tumors. The DNA in tissues of 10-day-old BD IX rats is alkylated by this ultimate carcinogen at the same sites as is DNA in mammalian cell cultures or DNA in solution. Similar proportions of the derivatives quantitated (O6-EtG, 7-EtG, 3-EtA, O2-EtT, O4EtT, O2EtC, and ethyl phosphotriesters) are found in each tissue examined 1 h after treatment with EtNU. Most of the ethylated bases are poorly removed (or, in the case of O4-EtT, not at all) from DNA in the brain, the target tissue of oncogenicity. A pool of five other tissues, excluding liver, exhibits a similar pattern of ethyl base persistence over a 75 h period. In contrast, liver apparently contains enzymes capable of removing all of the ethylated bases. In all tissues used, ethyl phosphotriesters are very stable. The observed kinetics imply that removal of ethylated bases would be complete within 10 days in liver, while over 50% of the chemically ethylated stable bases would persist in other tissues, including brain, for many weeks. We propose that any or all persistent promutagenic derivatives (O6-EtG, O2EtT, O4-EtT, O2-EtC) can be important in the initiation of carcinogenesis by somatic mutation, given that the damage DNA is expressed. The differing rates of removal of the ethyl purines and pyrimidines in brain, liver and pooled tissues imply that mammals possess multiple independent repair systems.