DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine.
[methyl-14C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mg/kg), 1,1-[14C]dimethylhydrazine (UDMH; 19 mg/kg), and [14C]dimethylnitrosamine (DMNA; 0.1 mg/kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the level of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis of purines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyl-3H]UDMH, the formation of 7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mg/kg. The methylation of DNA was strictly proportional to the dose. The data were used to compare the level of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could lead to a DNA methylation in the liver of about 6% of an average exposure to DMNA.
Sagelsdorff
P
P
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
Lutz
W K
WK
Schlatter
C
C
D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004127:Dimethylhydrazines / Q000633:toxicity*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008745:Methylation; D008763:Methylhydrazines / Q000633:toxicity*; D009152:Mutagenicity Tests; D010937:Plant Growth Regulators / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000633:toxicity*
D002250:Carbon Radioisotopes; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D010937:Plant Growth Regulators; D013386:Succinates; D004247:DNA; C014499:daminozide; D004128:Dimethylnitrosamine