title: Enzymatic removal of O6-ethylguanine versus stability of O4-ethylthymine in the DNA of rat tissues exposed to the carcinogen ethylnitrosourea: possible interference of guanine-O6 alkylation with 5-cytosine methylation in the DNA of replicating target cells.
abstract: In order to compare the kinetics of their enzymatic elimination from the DNA of liver, kidney, lung, and brain, the alkylation products O4-ethyl-2'-deoxythymidine (O4-EtdThd) and O6-ethyl-2'-deoxyguanosine (O6-EtdGuo) were quantitated by competitive radioimmunoassay over a period of 48 h after a single pulse of the carcinogen N-ethyl-N-nitrosourea (EtNU) applied i.p. to 10 and 28-day-old BDIX-rats. The content of O4-EtdThd in the DNA of all organs analyzed remained stable, while O6-EtdGuo (initially formed in DNA with 3-4 times higher frequency than O4-EtdThd) was rapidly removed from the DNA of liver, followed by lung and kidney, but persisted strongly in the DNA of brain. At 48 h after the EtNU-pulse, the O4-EtdThd content of liver DNA exceeded the O6-EtdGuo content by about a factor of 4. Since both O6-EtdGuo and O4-EtdThd are miscoding DNA lesions, the lack of enzymatic removal of O4-EtdThd is surprising in view of the apparent concern of cells to restore the integrity of the O6-position of guanine. Genetic consequences more specifically connected with the formation of O6-alkylguanine in DNA might be considered, e.g., possible alterations of gene expression via interference with enzymatic 5-cytosine methylation in 5'-CpG-3' sequences of newly replicated DNA.
mesh_terms: D000478:Alkylation; D000818:Animals; D002455:Cell Division; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D005038:Ethylnitrosourea / Q000378:metabolism*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D007700:Kinetics; D008745:Methylation; D009607:Nitrosourea Compounds / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D009607:Nitrosourea Compounds; C040384:4-ethylthymine; C007673:6-ethylguanine; D006147:Guanine; D003596:Cytosine; D004247:DNA; D005038:Ethylnitrosourea; D013941:Thymine