GENERATION AND PERSISTENCE OF CARCINOGEN-INDUCED REPAIR INTERMEDIATES IN RAT-LIVER DNA INVIVO

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  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (8) , 3238-3243
Abstract
Chromatographic separation of native DNA from DNA containing single-stranded regions was used to determine the relative concentrations of structural intermediates generated during chemically induced DNA repair. Single doses of each of 10 compounds were administered to rats. After periods ranging from 90 min to 13 days, hepatic DNA was isolated and analyzed by stepwise elution from benzoylated diethylaminoethyl cellulose with 1.0 M NaCl followed by caffeine solution. The compounds used were benzo(a)pyrene, CCl4, diethylnitrosamine, dimethylnitrosamine, ethyl methanesulfonate, galactosamine, N-hydroxy-2-acetylaminofluorene, methyl methanesulfonate, nitrosomorpholine and .beta.-propiolactone. Doses of the various agents and/or treatment times were restricted such that hepatic necrosis did not occur. No increase in the amount of caffeine-eluted DNA occurred after administration of CCl4 or galactosamine. All the remaining chemicals caused a dose-dependent increase in the proportion of hepatic DNA eluted from benzoylated diethylaminoethyl cellulose with caffeine. In most cases, the varying times required to produce maximal increase in the proportion of caffeine-eluted DNA could be related to the rate of metabolism of the carcinogens. Apparently, base excision repair is immediately operative and rapidly completed in rat liver. Reactions involved in the completion of nucleotide excision repair may be rate limiting, resulting in persistent structural damage to DNA. Implications of these findings for the use of benzoylated diethylaminoethyl cellulose chromatography as a carcinogen bioassay are considered.