It has been known for some time that hydrazine and its methyl and 1,1-dimethyl analogues induce inactivation of the copper-containing quinone-dependent plasma amine oxidase but that the activity recovers over time, suggesting metabolism of all three inhibitors. However, the mechanism responsible for loss and regain of activity has not been investigated. In this study a combination of enzyme studies under a controlled atmosphere along with model studies using 5-tert-butyl-2-hydroxy-1,4-benzoquinone to mimic the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor of the enzyme suggest that regain of enzyme activity represents two different O(2)-dependent processes. In the
case of methylhydrazine and 1,1-dimethylhydrazine, we propose that the inactive methylhydrazone/azo form of the enzyme slowly rehydrates and eliminates MeN=NH to give the triol cofactor form, which instantly reoxidizes to the catalytically active quinone form in the presence of O(2). Metabolism of methylhydrazine represents its conversion to CH(4) and N(2), and of 1,1-dimethylhydrazine to CH(2)=O, CH(4), and N(2). In the
case of hydrazine itself, however, we propose that the inactive hydrazone/azo form of the enzyme instead undergoes a slow decomposition, probably facilitated by the active-site copper, to give N(2) and a novel 5-desoxy resorcinol form of the cofactor. The latter undergoes a rapid, but noninstantaneous reoxygenation at C5 to restore the active cofactor form, also probably mediated by the active-site copper.