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Research ArticleArticle

Species-Dependent Differences in Monoamine Oxidase A and B-Catalyzed Oxidation of Various C4 Substituted 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl Derivatives

Hiroyuki Inoue, Kay Castagnoli, Cornelis Van der Schyf, Stéphane Mabic, Kazuo Igarashi and Neal Castagnoli Jr
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 856-864;
Hiroyuki Inoue
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Kay Castagnoli
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Cornelis Van der Schyf
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Stéphane Mabic
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Kazuo Igarashi
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Neal Castagnoli Jr
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Abstract

In an attempt to provide a better understanding of the scope and limitations of animal models used in some drug development programs and to further our understanding of potential metabolic bioactivation reactions, we have undertaken studies to profile the monoamine oxidase A and B (MAO-A and -B, respectively) activities in liver and brain mitochondrial preparations obtained from a variety of species using a series of 1-methyl-4-aryl-1,2,3,6-tetrahydropyridinyl substrates. Mitochondrial preparations were incubated with substrates at 37°C in the presence or absence of clorgyline, (R)-deprenyl, or a mixture of these two propargylamines to inhibit MAO-A, MAO-B, or both enzymes. The rates of formation of the corresponding dihydropyridinium metabolites were estimated spectrophotometrically. MAO-B was found to be the principal enzyme present in all tissues. Human liver displayed more MAO-A activity than the liver of any other species studied; subhuman primates displayed little or no detectable MAO-A activity. The properties of the preparations from rat liver were most similar to those from human liver with respect to the MAO-A/MAO-B ratios and the kinetic parameters of the four substrates used to profile enzymatic activity. The kinetic properties of mitochondrial preparations from bovine liver, a commonly used source of purified MAO-B preparations, were consistently different from all of the other species studied. The mitochondrial preparations from rabbit brain and liver also were unusual in that they displayed relatively low MAO activities. Additionally, these enzyme activities were considerably less susceptible to inhibition by clorgyline and (R)-deprenyl. Finally, an exceptionally low MAO-B liver/brainVmax/Km ratio was observed with the mitochondria obtained from the C57BL/6 mouse, an effect that may contribute to the susceptibility of this strain to the toxic effects of the parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Footnotes

  • Send reprint requests to: Dr. Neal Castagnoli, Jr., Department of Chemistry, Virginia Tech, Blacksburg, VA 24061-0212. E-mail: ncastagnoli{at}chemserver.chem.vt.edu

  • ↵1 This work was supported by Pharmacia & Upjohn, The Nitto Foundation, Japan, and the Harvey W. Peters Research Center for the Study of Parkinson’s Disease and Other Disorders of the Central Nervous System.

  • Abbreviations:
    MAO
    monoamine oxidase
    MPDP+
    1-methyl-4-phenyl-2,3-dihydropyridinium species
    MPP+
    1-methyl-4-phenylpyridinium species
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    GC
    gas chromatography
    MS
    mass spectrometry
    DMSO
    dimethyl sulfoxide
    UV-VIS
    ultraviolet-visible
    • Received May 4, 1999.
    • Accepted July 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

Species-Dependent Differences in Monoamine Oxidase A and B-Catalyzed Oxidation of Various C4 Substituted 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl Derivatives

Hiroyuki Inoue, Kay Castagnoli, Cornelis Van der Schyf, Stéphane Mabic, Kazuo Igarashi and Neal Castagnoli
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 856-864;

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Research ArticleArticle

Species-Dependent Differences in Monoamine Oxidase A and B-Catalyzed Oxidation of Various C4 Substituted 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinyl Derivatives

Hiroyuki Inoue, Kay Castagnoli, Cornelis Van der Schyf, Stéphane Mabic, Kazuo Igarashi and Neal Castagnoli
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 856-864;
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