PT  - JOURNAL ARTICLE
AU  - Hiroyuki Inoue
AU  - Kay Castagnoli
AU  - Cornelis Van der Schyf
AU  - Stéphane Mabic
AU  - Kazuo Igarashi
AU  - Neal Castagnoli, Jr
TI  - 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
DP  - 1999 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 856--864
VI  - 291
IP  - 2
4099  - http://jpet.aspetjournals.org/content/291/2/856.short
4100  - http://jpet.aspetjournals.org/content/291/2/856.full
SO  - J Pharmacol Exp Ther1999 Nov 01; 291
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics