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Methylation versus Ethylation of DNA in Target and Nontarget Tissues of Fischer 344 Rats Treated with N-Nitrosomethylethylamine¹

Laboratory of Neuropathology, Institute of Pathology, Universität Zürich, CH-8091 Zürich, Switzerland [E. V. H., F. G., P. K.]; Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute [L. K. K.]; and Program Resources, Inc. [V. N.] and LBI-Basic Research Program [W. L.], National Cancer Institute-Frederick Cancer Research Facility, Frederick, Maryland 21701

Bioactivation of N-nitrosomethylethylamine can be initiated by hydroxylation of either the methyl or ethyl moiety leading to an ethylating or methylating intermediate, respectively. This study was designed to determine which of these metabolic pathways predominates in vivo and to what extent DNA is alkylated in the target and nontarget tissues. Adult male Fischer 344 rats received a single i.p. or p.o. dose (4.4 mg/kg, 0.05 mmol/kg) of N-nitrosomethylethylamine, ¹⁴C-labeled in either the methyl or ethyl group (survival time, 4 h). DNA was analyzed by Sephasorb-HP chromatography following acid hydrolysis in 0.1 M HCl. Concentrations of 7-methylguanine in hepatic DNA were 170–200 times higher than those of 7-ethylguanine. This is approximately 2.6 times the 7-methylguanine:7-ethylguanine ratio of 68, observed when DNA is reacted in vitro with equimolar amounts of the direct alkylating agents N-nitrosomethylurea and N-nitrosoethylurea, suggesting that hydroxylation at the -position of the ethyl group of N-nitrosomethylethylamine proceeds at about 2.6 times the rate as at the methyl group. Concentrations of 7-methylguanine in liver were approximately 15 times higher than in kidney, 100 times higher than in esophagus, and 200 times higher than in lung. Addition of ethanol to the drinking water (5%) caused a slight interorgan shift in metabolism with a decrease in the 7-methylguanine ratio for liver:esophagus by 50% and an increase in the 7-methylguanine ratio for liver:kidney by 40%.

¹ Supported in part by the Swiss National Fund.

² To whom requests for reprints should be addressed, at Abteilung Neuropathologie, Universitätsspital, CH-8091, Zürich, Switzerland.

Received 6/11/85. Revised 11/ 7/85. Accepted 11/11/85.