Inhibition of bovine lung semicarbazide-sensitive amine oxidase (SSAO) by some hydrazine derivatives

Microsomal semicarbazide-sensitive amine oxidase (SSAO) from bovine lung was shown to be inhibit-ed by a number of hydrazine derivatives, but the mechanisms of inhibition were found to differ. Hydralazine behaved as an irreversible and partially time-dependent inhibitor with an IC50 value of 1 mu M under the conditions used. Phenylhydrazine was found to be a potent irreversible inhibitor of SSAO (IC50 30 nM). Semicarbazide behaved as a specific irreversible inhibitor (active-site-directed irreversible inhibitor) in first forming a non-covalent enzyme-semicarbazide complex (with a K-i value of 85 mu M), which then reacted to give an irreversibly inhibited enzyme species in a reaction defined by the first-order rate constant k(2) = 0.065 min(-1). Phenelzine behaved as a reversible inhibitor, but dialysis at 37 degrees C was found to be necessary to obtain full recovery of enzyme activity. The dependence of inhibition on phenelzine concentration was complex and consistent with multiple binding sites for this inhibitor. This diversity in the action of a family of compounds with the same functional group must be taken into account in attempts to design more specific inhibitors of this enzyme.