Studies of monoamine oxidases. Inhibition of bovine brain MAO in intact mitochondria by tricyclic antidepressant drugs.

Tricyclic antidepressant drugs (TCA) were found to reversibly inhibit monoamine oxidase (MAO) in intact mitochondria of beef brain cortex, I₅₀, values were in the range of 10^?4 to 10^?3 M, using chlorimipramine, amitriptyline, desimipramine, imipramine and doxepin. Unlike TCA inhibition reported for MAO in rabbit tissues, the inhibition observed with beef brain MAO was greater for the A-type enzyme, indicated by serotonin (5-HT) deamination, than for the B-type enzyme, indicated by phenylethylamine (PEA) deamination. Chlorimipramine was the most effective of the five tricyclic antidepressant drugs tested for the inhibition of 5-HT deamination, while amitriptyline was the most effective for inhibiting PEA deamination. Kinetic analyses also revealed marked differences in the interaction of the tricyclics with the A form and the B form of MAO. Inhibition was found to be of a mixed type by reciprocal plots, but Dixon plots indicated that the inhibition was parabolic with 5-HT and either linear or hyperbolic with PEA, depending on the TCA used. Mixed inhibitor studies were also carried out, combining a TCA with a selective (clorgyline or deprenyl) or a non-selective (tranylcypromine) MAO inhibitor. Such combinations did not result in a potentiation of inhibition of either the MAO-A or MAO-B type enzyme activity. The present results indicate that the inhibition of MAO may be of only minor significance in the therapeutic efficacy of TCA in the treatment of depression, especially in combined therapy. However, this conclusion must be tempered by the knowledge that there are marked variations in MAO properties from different enzyme sources, as evidenced by these results.