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© 1988 Oxford University Press

research-article

Formation and persistence of O6-(2-hydroxyethyl)-2'-deoxyguanosine in DNA of various rat tissues following a single dose of N-nitroso-N-(2-hydroxyethyl)urea. An immuno-slot-blot study

Barbara I. Ludeke and Paul Kleihues

Laboratory of Neuropathology, Institute of Pathology, University of Zurich CH-8091 Zürich, Switzerland

Rabbit antibodies against O6-(2-hydroxyethyl)-2'-deoxyguanosine (O6-HEdG) were used to develop a highly sensitive immuno-slot-blot assay for this promutagenic base which enabled the quantitation of ≥ 3.6 µmol O6-HEdG/mol deoxy-guanosine, corresponding to ≥ 5 fmol in a 3-µg DNA sample. This assay was used to study DNA hydroxyethylation by N-nitroso-N-(2-hydroxyethyl)urea (HENU) in adult male F344 rats. Initial amounts of O6-HEdG 2 h after a single i.v. dose of 50 mg/kg were highest in kidney (81 µmol O6HEdG/mol deoxyguanosine), followed by lung and liver (67 and 55 µmol/mol dG respectively). Formation of O6-HEdG in cerebral DNA was considerably lower (18 µmol O6-HEdG/mol deoxyguanosine), probably reflecting delayed crossing of the blood—brain barrier by HENU due to its hydrophilicity. The formation of O6-HEdG in liver and kidney was strictly proportional to dose over a range of 5–50 mg HENU/kg. Repair of O6-HEdG was very rapid in liver (apparent half-life, 12 h), and somewhat slower in kidney and lung (approximate half-life, 40 h and 48 h respectively). In contrast, 62% of the initial amount of O6-HEdG in cerebral DNA was still present after 7 days. Saturation of the hepatic O6-alkyl-guanine-DNA alkyltransferase by pretreatment with N-nitrosodimethylamine (20 mg/kg) almost completely inhibited the removal of O6-HEdG, indicating that O6-HEdG is predominantly repaired by this repair enzyme.


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