Triazene metabolism. I. The effect of substituents in the aryl group on the kinetics of enzyme-catalysed N-demethylation of 1-aryl-3,3-dimethyltriazenes

Abstract

A series of antitumor dimethylaryltriazenes (ArN=N∙NMe2) have been studied with respect to enzyme catalysed N-demethylation by liver microsomes and the Km values determined by Lineweaver–Burk treatement. The substituent in the aryl group of the triazene does not significantly effect the magnitude of Km, which is of the same order of magnitude as the Km for aminopyrine. On the other hand, dimethyltriazenes appear to have lower Km values for demethylation than the structurally similar dimethylnitrosamines. Monomethyltriazenes, the proposed active metabolites of the dimethyltriazenes, do not undergo appreciable demethylation in the presence of microsomes and it appears that the dimethyltriazenes only demethylate once during metabolism. Spontaneous formaldehyde release from the hydroxymethyltriazene in the presence of the Nash reagent prevented an analogous study of the metabolism of these compounds.