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Formation and persistence of O6-ethylguanine in genomic and transgene DNA in liver and brain of lambda(lacZ) transgenic mice treated with N-ethyl-N-nitrosourea.
Mientjes, E J; Hochleitner, K; Luiten-Schuite, A; van Delft, J H; Thomale, J; Berends, F; Rajewsky, M F; Lohman, P H; Baan, R A.
Afiliación
  • Mientjes EJ; Department of Molecular Toxicology, TNO Food and Nutrition Research Institute, Rijswijk, The Netherlands.
Carcinogenesis ; 17(11): 2449-54, 1996 Nov.
Article en En | MEDLINE | ID: mdl-8968062
LacZ transgenic mice are suitable for short-term mutagenicity studies in vivo. Mutagenicity in these mice is determined in the lacZ transgene. Since the lacZ gene is of bacterial origin the question has been raised whether DNA-adduct formation and repair in the transgene are comparable to those in total genomic DNA. Mice were treated with N-ethyl-N-nitrosourea (ENU) and killed at several time points following treatment. Some mice were pretreated with O6-benzylguanine to inactivate the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). O6-ethylguanine (O6-EtG) was determined in lacZ in liver and brain by means of a monoclonal antibody-based immunoaffinity assay. In addition, O6-EtG and N7-ethylguanine (N7-EtG) were assayed in total genomic DNA of liver and brain with an immunoslotblot procedure. In liver, the initial O6-EtG level in total genomic DNA was 1.6 times that in lacZ. The extent of repair of O6-EtG during the first 1.5 h after treatment was 2.1 times that in lacZ. At later time points, O6-EtG repair was the same. N7-EtG repair in genomic DNA was evident. In contrast to the liver, little repair of O6-EtG in total genomic and lacZ DNA occurred in the brain while N7-EtG was repaired. No initial difference in O6-EtG levels were found in lacZ and genomic brain DNA. These findings indicate that in the liver, total genomic DNA is more accessible than lacZ to ENU and/or the AGT protein, during the first 1.5 h following treatment. Because the difference in O6-EtG levels in the transgene and genomic DNA in the liver is restricted to the first 1.5 h after treatment, while the fixation of mutations occurs at later time points, O6-EtG-induced mutagenesis most likely is also very similar in both types of DNA.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / ADN / Etilnitrosourea / Guanina / Operón Lac / Hígado / Mutágenos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Carcinogenesis Año: 1996 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / ADN / Etilnitrosourea / Guanina / Operón Lac / Hígado / Mutágenos Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Carcinogenesis Año: 1996 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido