The decomposition and toxicity of dialkylnitrosamines in rats

Abstract

To find out which compounds are responsible for the acute hepatoxic action of dialkylnitrosamines, the metabolism in female rats of the following dialkylnitrosamines was studied dimethyl, di-ethyl, n-butylmethyl and tert.-butylmethyl. Some of each nitrosamine was excreted unchanged in urine and in expired air. The dependence of rate on dose was determined. Rates of decomposition in vivo were determined from the rates of fall of blood concentrations, and from rates of expiration of 14C-labelled CO2 from rats given the compounds labelled in methyl, ethyl or n-butyl groups. The results agreed well when allowance was made for excretion, and could be found with a coefficient of deviation of 6%. Labelled tert.-butyl groups of tert.-butylmethylnitrosamine, tert.-butylamine or 2-methylpropan-2-ol were not oxidized to labelled CO2. From the rates of expiration of labelled CO2 it was shown that the decomposition of all but the tert.-butyl compound obeyed the Michaelis-Menten equation; and that the oxidation of dimethylnitrosamine was inhibited competitively by the other three nitrosamines and by diethyl- and dimethyl-formamides. The oxidation of dietyl- and tert.-butylmethyl-nitrosamines was also inhibited competitively by diethylformamide. Dimethylnitrosamine and dimethylformamide inhibited much the same range of sites. From their action it appeared that the other three nitrosamines were oxidized at at least 2 types of site. The LD50 or ED50 values, or both, of the nitrosamines were determined. The tert. -butyl compound was without measurable necrotic activity. The ED50 values were unchanged by inhibitors that greatly increased the persistence of the nitrosamines in vivo. The results showed that the nitrosamines were not themselves toxic, and that the toxic agent must be a product of oxidation. Most possible metabolites could not be postulated as the toxic agents unless drastic assumptions were made. The results were consistent with the assumption that the toxic agent in each case was a diazoalkane, or a mono-alkylnitrosamine, orcarbonium ions formed from it.