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Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo


von Hofe, Eric; Kleihues, Paul; Keefer, Larry K (1986). Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo. Carcinogenesis, 7(8):1335-1337.

Abstract

At low doses, N-nitrosomethylethylamine (NMEA) selectively produces liver tumors in rats, whereas β-trideuterated NMEA also includes esophageal carcinomas under these conditions. Since deuteration is capable of retarding enzymic hydroxylation, these studies suggest that β-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 HCI, DNA purines were analysed by cation exchange chromatography. Of the major alkylpurines identified, 7-ethylguanine (7-etG) (6.7 μmol/mol guanine) and O6-ethylguanine (4.1 μmol/mol guanine) comprised 13 and 8% of the eluted radioactivity, respectively. 7-(2-HydroxyethyI)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 β-hydroxyethylated DNA bases observed suggest that this route of metabolism does not contribute significantly to the carcinogenicity of these compounds

Abstract

At low doses, N-nitrosomethylethylamine (NMEA) selectively produces liver tumors in rats, whereas β-trideuterated NMEA also includes esophageal carcinomas under these conditions. Since deuteration is capable of retarding enzymic hydroxylation, these studies suggest that β-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 HCI, DNA purines were analysed by cation exchange chromatography. Of the major alkylpurines identified, 7-ethylguanine (7-etG) (6.7 μmol/mol guanine) and O6-ethylguanine (4.1 μmol/mol guanine) comprised 13 and 8% of the eluted radioactivity, respectively. 7-(2-HydroxyethyI)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 β-hydroxyethylated DNA bases observed suggest that this route of metabolism does not contribute significantly to the carcinogenicity of these compounds

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 January 1986
Deposited On:18 Oct 2018 09:56
Last Modified:21 Oct 2018 04:41
Publisher:Oxford University Press
ISSN:0143-3334
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/carcin/7.8.1335
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093carcin781335 (Library Catalogue)

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