l -Deprenyl metabolism by the cytochrome P450 system in monkey (Cercopithecus aethiops) liver microsomes

• Published in: Xenobiotica Vol. 33; no. 2; pp. 181 - 195
• Main Authors: Dragoni, S., Bellik, L., Frosini, M., Sgaragli, G., Marini, S., Gervasi, P. G., Valoti, M.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 01.02.2003; Taylor & Francis
• Subjects: Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Blotting, Western; Cercopithecus aethiops; Chromatography, Gas; Cytochrome P-450 Enzyme System - metabolism; Dealkylation; Female; In Vitro Techniques; Kinetics; Medical sciences; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; Monoamine Oxidase Inhibitors - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Selegiline - metabolism; Selegiline; Cytochrome P450; Liver; Monkey; Neuroprotective agent; Microsome; Antiparkinson agent; In vitro; Activity metabolism relation; Vertebrata; Mammalia; Animal; Primates; L stereoisomer
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/0049825021000048827

1. The aim was to clarify the kinetic and cytochrome P450 (CYP) enzymes involved in l -deprenyl metabolism by liver microsomal preparations from African green monkeys, an animal model extensively used in the study of Parkinson's disease. 2. CYP levels and monoxygenase activities were similar to those observed in microsomes from other monkey strains. The enzyme kinetics of both l -methamphetamine and l -nordeprenyl formation were characterized by a high- and low-affinity component. For l -methamphetamine, the apparent K m 1 and K m 2 were 1.07 ±0.01 and 350 ±2.7 µM, and V max 1 and V max 2 were 4.70 ±0.01 and 8.9 ±0.02 nmol min <1 mg protein <1, respectively. For l -nordeprenyl, K m 1 and K m 2 were 0.96 ±0.05 and 168 ±15 µM, and V max 1 and V max 2 were 3.34 ±0.02 and 3.91 ±0.02 nmol min <1 mg protein <1, respectively The ratio V max / K m for both metabolites was 2 orders of magnitude higher for the low K m component than for the high K m, suggesting that the former component is the major determinant of l -deprenyl N-dealkylation. At 15 µM l -deprenyl, both ketoconazole and 8-methoxypsoralen significantly inhibited l -methamphetamine and l -nordeprenyl formation, indicating that CYP3A and CYP2A enzymes were involved in both reactions. At 500 µM l -deprenyl, however, inhibition studies suggest the involvement of CYP1A and 2D enzymes. 3. The metabolism of l -deprenyl by monkey liver microsomes is very efficient, indicating that CYP-dependent metabolism is relevant and could contribute to neuroprotection in primate models of Parkinson's disease.