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.
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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)
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Chemical References |
- Carbon Radioisotopes
- Nitrosamines
- methylethylnitrosamine
- Carbon Dioxide
- 7-ethylguanine
- Guanine
- 7-methylguanine
- DNA
- O-(6)-methylguanine
- Deuterium
- Dimethylnitrosamine
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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
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