Beta-deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus.

Abstract

While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its beta-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 ethylated purines in the DNA of various organs were determined by radio-chromatography on Sephasorb-HP columns. When compared to previous data using undeuterated NEMA, 7-methylguanine levels were found to be reduced by approximately 30% in liver 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. O6-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-d3 relative to undeuterated NEMA in that organ. Since pharmacokinetic studies have shown that beta-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.

• Authors: E von Hofe, I Schmerold, R W Nims, L K Keefer, E J Reist, P Kleihues
• Journal: Carcinogenesis (Carcinogenesis) Vol. 12 Issue 4 Pg. 545-9 (Apr 1991) ISSN: 0143-3334 [Print] England
• PMID: 1901522 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Carbon Radioisotopes
• Nitrosamines
• methylethylnitrosamine
• Carbon Dioxide
• 7-ethylguanine
• Guanine
• 7-methylguanine
• DNA
• O-(6)-methylguanine
• Deuterium
• Dimethylnitrosamine

Topics

• Animals
• Carbon Dioxide (metabolism)
• Carbon Radioisotopes
• Chromatography (methods)
• DNA (metabolism)
• Deuterium (metabolism)
• Dimethylnitrosamine (analogs & derivatives, metabolism)
• Esophagus (metabolism)
• Guanine (analogs & derivatives, metabolism)
• Kidney (metabolism)
• Liver (metabolism)
• Lung (metabolism)
• Male
• Methylation
• Microsomes, Liver (metabolism)
• Nitrosamines (metabolism)
• Rats
• Rats, Inbred F344