Studies of monoamine oxidases

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

“…The 150 values were 9, 30 and 100 p~ for mouse brain and 20,60 and 120 p~ for guinea-pig brain with PEA, benzylamine and 5-HT as substrates, respectively. This preferential inhibition of type B M A 0 accords with previous studies on rabbit tissues (Roth & Gillis l974,1975b), but is at variance with studies using bovine brain (Achee & Gabay 1979). However, Achee & Gabay (1977) reported that inhibition of bovine brain mitochondria1 M A 0 by selegiline (( -)-deprenyl) and pargyline, which are selective irreversible inhibitors of type B MAO, failed to show the expected double sigmoid plot of inhibition against the logarithm of the inhibitor concentration when tyramine was used as the substrate, so it may be unsound to apply the normal A/B distinction to this particular tissue.…”

“…However, these plots were generally not linear; with 5-HT, inhibition was always greater at higher inhibitor concentrations than would have been expected from the extent of inhibition seen at low concentrations, whereas the converse was usually found with benzylamine or PEA. Similar abnormalities in this type of plot were reported by Achee & Gabay (1979) for the inhibition by tricyclic antidepressants of 5-HT or PEA oxidation by bovine liver mitochondria. Nevertheless, with the single exception of iprindole with benzylamine as substrate, all the compounds were more potent against the type B M A 0 substrates (PEA and benzylamine) than against the type A substrate (5-HT).…”

“…With the rat brain enzyme and 5-HT (10-200 p~, K, about 70 p~) , amitriptyline at 40 or 100 p~ was a competitive inhibitor with a Ki of 130 p~. Amitriptyline has been previously shown to act as a competitive inhibitor of 5-HT oxidation by bovine brain M A 0 (Achee & Gabay 1979). With rat brain and PEA (1.25-10 p~, K, about 5 p~) inhibition by amitnptyline at 5 , 10, or 20 p~ was almost pure non-competitive with a K, of 7-9 p~, whereas with mouse liver and PEA (2.5-20 p~, K, about 11 p~) , inhibition was close to pure non-competitive with 5 p~ amitriptyline but became mixed (an increase in K, as well as a further decrease in V, , , ) at 10 or 20 p~ amitriptyline.…”

“…The actual extent of inhibition found in these kinetic studies with MAO-B substrates accorded well with the I50 values in Tables 1 and 2, but the confusing kinetic patterns are typical of those described in previous literature. Thus, for the inhibition of PEA oxidation by amitriptyline, mixed inhibition was found with bovine brain (Achee & Gabay 1979), mixed (but close to competitive) inhibition with rabbit brain (Roth & Gillis 1975b), non-competitive inhibition with human brain (Roth 1976) and, with human platelets, inhibition varying from near uncompetitive at a low concentration of amitriptyline to pure non-competitive at a high concentration (Edwards & Burns 1974). Benzylamine oxidation by human platelets was inhibited competitively by amitriptyline, irrespective of concentration, but the secondary plot of slope against benzylamine concentration was markedly nonlinear (Edwards & Burns 1974).…”

“…However, there are many inconsistencies among the reported inhibitory potencies, and it is still unclear whether this inhibition is relevant to the clinical effectiveness of these compounds (Sulser et a1 1978;Sulser & Mobley 1980). Depending on which tissue is used as the source of the enzyme both the A form (Achee & Gabay 1979) and the B form (Roth & Gillis 1975a,b) of M A 0 have been reported to be the more susceptible to inhibition, and even with tissues in which the enzyme is almost exclusively B type, such as human platelets, sensitivity to inhibition depends markedly on which substrate is used (Edwards & Burns 1974). In an attempt to clarify some of these discrepancies we have examined both the effect of the choice of tissue and the choice of substrate on the inhibition of M A 0 by five of the more commonly used tricyclic antidepressants.…”