While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its -trideuterated derivative, N-nitroso([2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]-and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and

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... hylated purines in the DNA of various organs were determined by radiochromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-niethylguanine levelswerefoundtobereducedby 30%inliverandkldney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O6-Methlguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine In hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that -trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissues (1991). -Deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus. Carcinogenesis, 12(4):545-549. While iV-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its /3-trideuterated derivative, W-nitroso([2-Z) 3 ]ethyl)methylaniine (NEMA-d 3 ), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14 C]-and [l-ethyl-14 C]-labeled NEMA-d 3 were administered to adult male Fischer 344 rats as a single i.p. dose (0.05 mmol/kg; 4 h survival). Levels of methylated and ethylated purities in the DNA of various organs were determined by radiochromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-methylguanme levels were found to be reduced by -30% in Hver and kidney, but were 160% greater in esophagus. This resulted in a decrease in the 7-methylguanine ratio for liver/esophagus from 109 to 29. O*-Methylguanine was diminished in liver and kidney, but levels in lung and esophagus were too low for quantitative detection. Similarly, deuteration led to an 18% decrease of 7-ethylguanine in hepatic DNA. The observed increase in esophageal DNA methylation correlates with the increased carcinogenicity of NEMA-d 3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that /3-trideuteration of NEMA does not alter its bioavailability, the data suggest that the observed shift in target organ results from isotopically-induced changes in the balance among competing metabolic pathways in different rat tissues.