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Species Differences in the Selective Inhibition of Monoamine Oxidase (1-methyl-2-phenylethyl)hydrazine and its Potentiation by Cyanide

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Abstract

The potentiating effects of cyanide on the inhibition of rat liver mitochondrial monoamine oxidase-A & B and of ox liver mitochondrial MAO-B by pheniprazine [(1-methyl-2-phenylethyl)hydrazine] has been studied. Pheniprazine was shown to behave as a mechanism-based MAO inhibitor. For rat liver MAO-B, the initial non-covalent step was characterized by dissociation constant (K i) of 2450 nM and the first-order rate constant (k +2) for the covalent adduct formation was 0.16 min−1. As a reversible inhibitor it was selective towards rat liver MAO-A (K i = 420 nM) but the rate of irreversible inhibition of that enzyme was considerably slower (k +2 =  0.06 min−1). MAO-B from ox liver more closely resembled MAO-A from the rat in sensitivity to reversible inhibition by pheniprazine (K i = 450 nm) but it was closer to rat liver MAO-B in rate of irreversible inhibition (k +2 = 0.29 min−1). The K i values were significantly decreased in the presence of KCN but there was little effect on the k +2 values. However, sensitivities of the different enzymes to KCN varied widely and considerably higher concentrations of KCN were required for this effect to be apparent with the rat liver mitochondrial MAO-A than with MAO-B from rat and ox liver. The kinetic behaviour of cyanide activation was consistent with partial (non-essential) competitive activation in all cases.

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Acknowledgments

We are grateful to the Health Research Board and Forbairt, Ireland, for support for this work, to the Government of Libya for a grant in support of ZBR and to the EC ERASMUS Programme for the support of MLW.

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Authors and Affiliations

  1. Department of Biochemistry, Trinity College, Dublin, 2, Ireland

    Zakia Ben Ramadan, Maria L. Wrang & Keith F. Tipton

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  1. Zakia Ben Ramadan
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  2. Maria L. Wrang
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  3. Keith F. Tipton
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Correspondence to Keith F. Tipton.

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Special issue dedicated to Dr. Moussa Youdim.

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Ramadan, Z.B., Wrang, M.L. & Tipton, K.F. Species Differences in the Selective Inhibition of Monoamine Oxidase (1-methyl-2-phenylethyl)hydrazine and its Potentiation by Cyanide. Neurochem Res 32, 1783–1790 (2007). https://doi.org/10.1007/s11064-007-9309-x

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