HUMAN LIVER MITOCHONDRIAL MONOAMINE OXIDASE .3. KINETIC STUDIES CONCERNING TIME-DEPENDENT INHIBITIONS

Kinetic data indicate that dissimilar mechanisms are responsible for in vitro inhibitions of human liver mitochondrial monoamine oxidase by agents representative of three major categories of inhibitors and that the apparent potency of a given inhibitor depends upon several conditions of the determinations. Iproniazid and isopropylhydrazine inhibit the enzyme by a time-dependent mechanism. While substrates protect the enzyme from such time-dependent inhibitions, the kinetics of substrate oxidations by partially inactivated enzyme indicate noncompetitive inhibitions with respect to substrate. The time-dependent interactions of iproniazid or isopropylhydrazine with the enzymes are not simple second-order reactions, but appear to result from catalytic conversions of these hydrazines to noncompetitive inhibitors. Unlike these hydrazines, 2-phenylcyclopropylamines and 2-propynylamines are instantaneous, competitive inhibitors as well as time-dependent noncompetitive inhibitors. The time-dependent inhibitions are in keeping with simple second-order reactions. The effect of pH upon inhibitor constants of the instantaneous interactions and the second-order rate constants of the time-dependent reactions suggest that un-ionized species of these amine inhibitors interact with the enzyme. In respect to both types of inhibition, the d isomer of tranylcypromine may be considered to be primarily responsible for the inhibitory effects of the racemic mixture. p-Mercuribenzoate inhibits the enzyme activity by a time-dependent mechanism, consistent with a simple second-order reaction. This sulfhydryl reagent has no instantaneous effect upon the enzyme activity, however, and the kinetics of substrate oxidation by partially inactivated enzyme indicate the inhibition to be competitive with respect to substrate. © 1969, American Chemical Society. All rights reserved.