AN UNEXPECTED PATHWAY FOR THE METABOLIC-DEGRADATION OF 1,3-DIALKYL-3-ACYLTRIAZENES

In the presence of NADPH, rat liver microsomes catalyzed the degradati on of a series of 1,3-dialkyl-3-acyltriazenes, and the extent of the r eaction was correlated with compound lipophilicity. In the case of two methylcarbamoyltriazenes, -chloroethyl)-3-benzyl-3-(methylcarbamoyl)t riazene (CBzM) and -chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM), microsomal metabolites were isolated. Identification of the CBz M metabolites as 2-chloroethyl)-3-benzyl-3-(hydroxymethylcarbamoyl) tr iazene and 1-(2-chloroethyl)-3-benzyl-3-carbamoyltriazene, and the CMM metabolite as ethyl)-3-methyl-3-(hydroxymethylcarbamoyl)triazene indi cated that the first metabolic step involves hydroxylation of the meth ylcarbamoyl substituent. Detailed studies of the metabolism of CBzM in dicated that the K(m) for the reaction was 84 muM, and that metabolism was more efficient if microsomes were prepared from male than from fe male rats. During prolonged incubation, the metabolites of CBzM were a lso degraded. The degradation of CBzM and its metabolites was inhibite d by SKF-525A and metyrapone, suggesting the involvement of a cytochro me P450 isozyme, and supporting the hypothesis that the process is oxi dative rather than hydrolytic in both cases. Metabolic oxidation repre sents an alternative pathway to chemical or enzymatic hydrolysis for t he in vivo decomposition of methylcarbamoyl)triazenes. This mechanism may ultimately explain the antitumor efficacy and low acute toxicity o f selected compounds.