Use of diethyldithiocarbamate as a probe to detect stable intermediates during the decomposition of several mutagenic and nonmutagenic N-nitroso compounds

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Abstract
By showing that methyldiethyldithiocarbamate is formed from the reaction of methylnitrosourea and disulfiram, we demonstrated in previous experiments that one of the anticarcinogenic/antimutagenic mechanisms of disulfiram is the scavenging of reactive species. We propose that this reaction may be employed additionally as a model for elucidating the following: (a) possible reactions between alkylating species and nucleophilic sites within the cell, and (b) the existence of stable intermediates during the metabolism of N-nitroso compounds. With structurally related pairs of nitrosoureas (n-propyl/isopropyl; cyclopropyl/allyl; 2-phenylethyl/1-phenylethyl), for which each alkylating group of the first compound can spontaneously rearrange to form the alkylating group of the second isomer, we investigated whether the alkylation proceeds via a monomolecular (sn1) or a bimolecular substitution (sn2). For this, we comparatively determined the relative mutagenic activities of each isomer in Salmonella typhimurium TA 1535, as well as their reactivities towards diethyldithiocarbamate (DDTC) by identifying the reaction products. These studies were aimed at revealing the possible formation of a free carbonium ion in the decomposition of several nitrosoureas in the rat liver supernatant fraction. Our system showed that DDTC reacts by two competing mechanisms: attack at the diazonium ion and at the free carbonium ion. Therefore the striking differences which were observed in the mutagenic potency of cyclopropylnitrosourea and N-nitrosoallylurea as well as of N-nitroso-2-phenylethylurea and N-nitroso-1-phenylethylurea cannot be explained only by the different electrophilic reactivities of the respective intermediates.

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