Dramatic species differences in the susceptibility of monoamine oxidase B to a group of powerful inhibitors

Oxadiazolones and oxadiazolethiones are potent, reversible competitive inhibitors of MAO B in rat brain mitochondria. We have compared the K_i values of six of these inhibitors toward MAO B from rat, human and beef liver mitochondria, using benzylamine as substrate. Unexpectedly, their inhibitory potency varies by 3 to 4 orders of magnitude between rat and beef liver MAO B, whereas the inhibition of the rat and human liver enzymes is quite similar. Examples are 5-(4-benzyl-oxyphenyl)-3-(2-cyano-ethyl)-1,3,4- oxadiazole-2(3H)-thione, with K at 30° of 0.5 nM for rat, 0.8 nM for human, and 1,830 nM for beef liver mitochondria and 5-(4-benzyl-oxyphenyl)-3-(2-hydroxyethyl)-1,3,4- oxadiazol-2(3H)-thione, with K_i values of 1.2, 1.1 and 1,320 nM for MAO B from these three sources. Since solubilized and membrane-bound enzymes had similar sensitivities to the inhibitors, the differences seen must arise from differences in the amino acid sequences of the three enzymes.