Beta-deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus.
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.
von Hofe
E
E
Laboratory of Neuropathology, University of Zürich, Switzerland.
Schmerold
I
I
Nims
R W
RW
Keefer
L K
LK
Reist
E J
EJ
Kleihues
P
P
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002845:Chromatography / Q000379:methods; D004247:DNA / Q000378:metabolism*; D003903:Deuterium / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000378:metabolism; D004947:Esophagus / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D002250:Carbon Radioisotopes; D009602:Nitrosamines; C017510:methylethylnitrosamine; D002245:Carbon Dioxide; C022007:7-ethylguanine; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine; D003903:Deuterium; D004128:Dimethylnitrosamine