Tetraformyltrisazine and hydrazine-induced methylation of liver DNA guanine

Abstract

Hydrazine induces methylation of target-organ DNA guanine; the methylation mechanism was proposed to involve reaction of hydrazine with endogenous formaldehyde. One possible condensation product of hydrazine and formaldehyde is tetraformyltrisazine (TFT). TFT administered to Sprague--Dawley rats produced 7-methylguanine and O⁶-methylguanine in liver DNA at rates of formation and times to maximal methylguanine levels similar to those observed after hydrazine administration. TFT administration, however, resulted in greater amounts of methylguanines than did hydrazine on a molar basis, suggesting that TFT is perhaps a more proximal intermediate in hydrazine-induced methylation. The metabolic activation of TFT and hydrazine-plus-formaldehyde to methylating intermediates was detectable in in vitro systems containing as little as 0.2 mM TFT or 1 mM hydrazine-plus-formaldehyde, the lowest concentrations yet tested. The other major condensation product of hydrazine and formaldehyde, formalazine, also methylated liver DNA in vivo, but this polymer forms under conditions that would not be expected under in vivo administration of hydrazine. A novel pathway is proposed for the generation of a carbocation in hepatocytes exposed to hydrazine, consisting of condensation of hydrazine and formaldehyde to form TFT or formaldazine and/or formaldehyde hydrozymethylhydrazone and involves methylazo-methanol as an intermediate.