Studies on lung tumours. III. Oxidative metabolism of dimethylnitrosamine by rodent and human lung tissue.
The oxidative metabolism of the carcinogen dimethylnitrosamine (DMN) was studied in mouse, rat, hamster and human respiratory tissue. [14C]DMN was purified by Dowex-1-bisulfite column chromatography to remove a contaminant (probably [14C]formaldehyde) interfering with the enzyme assay. Since formaldehyde and methyl carbonium ions - yielding methanol with water - are considered to be the primary products of DMN metabolism, tissue slices were assayed for the production of [14C]CO2 from 14C-labelled methanol, formaldehyde, formate, and DMN. Oxidation of formaldehyde to formate was not, but oxidation of formate to CO2 was very much rate-limiting. This rate-limiting step was circumvented by introducing quantitative chemical oxidation of formate to CO2 by mercury(II)chloride following the enzymic reaction. Since oxidation of methanol to CO2 proved to be insignificant, production of CO2 from DMN by lung tissue enzymes and HgCl2 may serve as a parameter for N-demethylating activity and the production of the suspected carcinogenically active methyl carbonium ions. The DMN-N-demethylating activities of lung tissue slices of two mouse strains with widely different susceptibilities to formation of lung adenomas by DMN differed significantly, but the difference seemed too small to explain the divergence in tumourigenic response. The enzymatic activities decreased in hamster bronchus, hamster trachea, hamster lung, GRS/A mouse lung, C3Hf/A mouse lung, human lung, Sprague-Dawley rat lung, in that order. The reported resistance of the hamster respiratory system to tumour induction by DMN may therefore not be due to poor DMN-N-demethylating capacity.
D000368:Aged; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D006224:Cricetinae; D004128:Dimethylnitrosamine / Q000378:metabolism*; D005260:Female; D005557:Formaldehyde / Q000378:metabolism; D005561:Formates / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000494:pharmacology; D000432:Methanol / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D014132:Trachea / Q000378:metabolism
D005561:Formates; D009602:Nitrosamines; D002245:Carbon Dioxide; D005557:Formaldehyde; D008628:Mercury; D004128:Dimethylnitrosamine; D000432:Methanol