DNA methylation in various rat tissues by the esophageal carcinogen N-nitrosomethyl-n-amylamine and six of its positional isomers.
The major pathway for the bioactivation of asymmetric N-nitrosomethylalkylamines involves cytochrome P-450 catalyzed alpha-C hydroxylation of the alkyl moiety opposite the methyl group, leading to the formation of a methanediazonium ion as the ultimate carcinogen. In the present study we have investigated the effect of the steric configuration of the pentyl chain on the bioactivation of N-nitrosomethylpentylamines in vivo. N-Nitrosomethyl-n-amylamine, a potent esophageal carcinogen, and six of its positional isomers were synthesized by nitrosation of the precursor amines. Overall yields and proportions of the respective Z- and E-isomers reflected the steric hindrance at the alpha-carbon of the pentyl groups. The extent of DNA methylation in various rat tissues after a single dose (0.1 mmol/kg; 6-h survival) of the isomers was determined by cation-exchange HPLC with fluorescence detection. (1) Among extrahepatic tissues, methylpurine concentrations were highest in esophagus, followed by the nasal and tracheal mucosa and lung. In these tissues, which are phylogenetically derived from the rat ventral entoderm, the relative extent of DNA methylation followed the same pattern for all isomers. (2) In the esophagus, formation of O6-methylguanine (O6-meG) was observed only for isomers with an unsubstituted alpha-methylene in the pentyl moiety, i.e., N-nitrosomethylisoamylamine, -n-amylamine, -(2-methylbutyl)amine, and -(2,2-dimethylpropyl)amine. (3) In trachea, methylated purines were also detectable after administration of the alpha-substituted isomer, N-nitrosomethyl(1-methylbutyl)amine. (4) Only nasal mucosa and lung were capable of bioactivating N-nitrosomethyl(1,2-dimethylpropyl)amine.(ABSTRACT TRUNCATED AT 250 WORDS)
Ji
C A
CA
Institute of Pathology, University Hospital, Zürich, Switzerland.
Ludeke
B I
BI
Kleihues
P
P
Wiessler
M
M
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000139:chemically induced; D004947:Esophagus / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D008297:Male; D008745:Methylation; D009297:Nasal Mucosa / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000378:metabolism
D002273:Carcinogens; D009602:Nitrosamines; C025033:N-amyl-N-methylnitrosamine; D006147:Guanine; D004247:DNA