Repair of ethylnitrosourea-induced DNA damage in the newborn rat. I. Alkali-labile lesions and in situ breaks.
The extreme sensitivity of the developing rat brain to tumor induction by N-ethyl-N-nitrosourea (ENU) has been ascribed to the relatively inefficient repair of the presumed promutagenic lesion O6-ethylguanine from brain DNA. We have compared the brain of the newborn rat with liver, kidney and lung with respect to the repair of other types of DNA lesions that ENU induces, namely single strand breaks and alkali-labile lesions. The induction and repair or loss of these lesions has been analysed by alkaline sucrose gradient sedimentation using both mild as well as strong alkaline hydrolysis conditions. We found that ENU induces few lesions in the DNA of various organs that are detectable as breaks after mild alkaline hydrolysis. 24 h after ENU treatment such lesions are no longer detectable in brain DNA, while they are detectable in the DNA from other organs up to 10 days after ENU treatment. The number of ENU-induced lesions, detectable as breaks after strong alkaline hydrolysis, is far larger. These lesions were persistent in kidney DNA, disappeared slowly from liver DNA (t(1/2) = about 10 days), and more rapidly from brain and lung DNA (t(1/2) = 2-3 days). The latter result seems to be in contradiction with various reports that a large fraction of the ENU-induced alkali-labile lesions are stable in vivo. This difference between our results and those of others might be due to a difference between proliferating and non-proliferating cells. Whether the alkali-labile lesions are removed from brain and lung DNA by a specific repair mechanism or by other causes remains to be investigated.
Heyting
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Division of Chemical Carcinogenesis, Antoni Van Leeuwenhoek-Huis, Netherlands Cancer Institute, Amsterdam.
Huigen
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Den Engelse
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D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012972:Sodium Hydroxide / Q000494:pharmacology
D000477:Alkylating Agents; C022007:7-ethylguanine; C022595:3-ethyladenine; C007673:6-ethylguanine; D012972:Sodium Hydroxide; D006147:Guanine; D004247:DNA; D000225:Adenine; D005038:Ethylnitrosourea