Temporary inactivation of plasma amine oxidase by alkylhydrazines. A combined enzyme/model study implicates cofactor reduction/reoxidation but cofactor deoxygenation and subsequent reoxygenation in the case of hydrazine itself

It has been known for some time that hydrazine and its methyl and 1,1-dimet hyl analogues induce inactivation of the copper-containing quinone-dependen t 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 com bination of enzyme studies under a controlled atmosphere along with model s tudies using 5-tert-butyl-2-hydroxy-1,4-benzoquinone to mimic the 2,4,5-tri hydroxyphenylalanine quinone (TPQ) cofactor of the enzyme suggest that rega in of enzyme activity represents two different Os-dependent processes. In t he case of methylhydrazine and 1,1-dimethylhydrazine, we propose that the i nactive methyl hydrazone/azo form of the enzyme slowly rehydrates and elimi nates 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 CH4 and N-2, and of 1,1-dimet hylhydrazine to CH2=O, CH4, and N-2. In the case of hydrazine itself, howev er, we propose that the inactive hydrazone/azo form of the enzyme instead u ndergoes a slow decomposition, probably facilitated by the active-site copp er, to give Nz and a novel 5-desoxy resorcinol form of the cofactor. The la tter undergoes a rapid, but noninstantaneous reoxygenation at C5 to restore the active cofactor form, also probably mediated by the active-site copper .