Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo.
At low doses, N-nitrosomethylethylamine (NMEA) selectively produces liver tumors in rats, whereas beta-trideuterated NMEA also includes esophageal carcinomas under these conditions. Since deuteration is capable of retarding enzymic hydroxylation, these studies suggest that beta-hydroxylation plays a significant role in the organ specificity of NMEA. To test the hypothesis that this metabolic pathway occurs in vivo to yield a hydroxyethylating intermediate, we have determined the extent of hydroxyethylation of hepatic DNA in male Fischer 344 rats following a single i.p. injection of [1-ethyl-14C]NMEA (6.3 mg/kg, 4 h survival). After hydrolysis in 0.1 M HCl, DNA purines were analysed by cation exchange chromatography. Of the major alkylpurines identified, 7-ethylguanine (7-etG) (6.7 mumol/mol guanine) and O6-ethylguanine (4.1 mumol/mol guanine) comprised 13 and 8% of the eluted radioactivity, respectively. 7-(2-Hydroxyethyl)guanine (7-heG) was the only hydroxyethyl adduct detectable, and comprised less than 2% of the amount of 7-etG. 3-Ethylguanine and 3- and 7-ethyladenine were also identified as products of NMEA metabolism. Similar analyses were carried out on hepatic DNA from rats treated with N-nitrosodi[1-14C]ethylamine (6.9 mg/kg, 4 h survival). Only trace amounts of 7-heG could be detected. The very low concentrations of beta-hydroxyethylated DNA bases observed suggest that this route of metabolism does not contribute significantly to the carcinogenicity of these compounds.
D000478:Alkylation; D000818:Animals; D002250:Carbon Radioisotopes; D004247:DNA / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D002250:Carbon Radioisotopes; C017510:methylethylnitrosamine; D004052:Diethylnitrosamine; D004247:DNA; D004128:Dimethylnitrosamine