Organ specificity, metabolism and reaction with DNA of aliphatic nitrosomethylalkylamines.
Aliphatic nitrosomethylalkylamines are carcinogens with a remarkable organ specificity in rats, the principal targets being liver, oesophagus and bladder. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6-h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (NDMA, C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7- and O6-methylguanine; 7-meGua and O6-meGua) were determined by cation-exchange high-performance liquid chromatography with fluorescence detection. Highest levels of hepatic DNA methylation were found with NDMA (C1) and N-nitrosoethylmethylamine (NEMA, C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length from C1 to C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the most effective agents being the butyl and pentyl derivatives (C4 and C5). Levels of DNA methylation in bladder epithelium were close to the limit of detection (C6,C9,C10,C12) and there was no apparent correlation with carcinogenicity. It is concluded that initiation of malignant transformation by DNA methylation alone (through hydroxylation of the nitrosamine at the methylene alpha-carbon) could be operative for C1-C5. For the higher homologues, this type of DNA modification is insufficient to explain the complex pattern of tissue specificity.
Kleihues
P
P
Department of Pathology, University of Zürich, Switzerland.
von Hofe
E
E
Schmerold
I
I
Keefer
L K
LK
Lijinsky
W
W
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008745:Methylation; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002273:Carcinogens; D009602:Nitrosamines; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine