The inhibition of monoamine oxidase by tricyclic antidepressants: the influence of the nature of the substrate and the source of the enzyme

Abstract

Five tricyclic antidepressants, amitriptyline, clomipramine, desipramine, imipramine and iprindole, have comparable potencies as inhibitors of monoamine oxidase in rodent brain and liver. With rodent brain, potency was always greater with phenethylamine as substrate than with benzylamine, and was generally least with 5-HT. With mouse liver, in which monoamine oxidase is mainly B type, potency with tyramine and dopamine as substrates was close to that found with phenethylamine. The kinetics of inhibition varied with both the substrate and the tissue, and were inconsistent with a simple ping-pong model for substrate oxidation. The relevance of these observations to clinical effectiveness is discussed.

Interaction of psychotropic drugs with monoamine oxidase in rat brain

“…It has been demonstrated that tricyclic antidepressants, such as imipramine, have an inhibitory activity towards MAO and particularly MAO-B (Green & McGachy 1987). However, systematic studies are lacking.…”

The effect of some tricyclic antidepressants on the inhibition of mouse brain monoamine oxidase in-vivo by phenelzine

“…Assuming this is also true in mice for these antidepressants of broadly similar structure, the expected maximum brain levels from a dose of 20 mg kg-' would be around 60 p~. At such concentrations in-vitro these compounds would be expected to produce around 30% inhibition of 5-HT oxidation but around 70% or more inhibition of PEA oxidation (Green & McGachy 1987).…”

“…After 24 h the mice were killed and their brains were homogenized in 0.1 M sodium phosphate buffer (pH 7.4). M A 0 was assayed using [I4C]5-HT (1 1.5 p~) or ['4C]2-phenethylamine (PEA) ( 5 p~) as substrates as described by Green & McGachy (1987). Each assay mixture (total volume 2 mL) contained 5 mg brain tissue when 5hydroxytryptamine (5-HT) was used, but only 0.5 mg when phenethylamine was used.…”

“…A variety of tricyclic antidepressants have been shown to be moderately active inhibitors of brain monoamine oxidase (EC 1.4.3.4.,MAO) in-vitro (Roth & Gillis 1975;Roth 1978;Achee & Gabay 1979;Green & McGachy 1987), but it is still unclear whether this inhibition is relevant to their clinical effectiveness (Sulser & Mobley 1980). Regular administration of some of these compounds has been reported to cause slight inhibition of brain M A 0 in rats (Arora & Meltzer 1976) and to reduce blood platelet M A 0 in man (Sullivan et al 1977).…”

Mitochondrial Functions in Mood Disorders

“…However, in vivo inhibition of the human platelet MAO-B in the patients taking tricyclic antidepressants was not confirmed by others [190][191]. Five tricyclic antidepressants, amitriptyline, clomipramine, desipramine, imipramine and iprindole, have comparable potencies as inhibitors of MAO in rodent brain and liver [192]. These antidepressants have been shown to partially protect mouse brain MAO in vivo from the irreversible enzyme inhibition produced by subsequent injection of phenelzine [193].…”