l-Deprenyl metabolism by the cytochrome P450 system in monkey (Cercopithecus aethiops) liver microsomes.
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(m1) and K(m2) were 1.07 +/- 0.01 and 350 +/- 2.7 micro M, and V(max1) and V(max2) were 4.70 +/- 0.01 and 8.9 +/- 0.02 nmol min(-1) mg protein(-1), respectively. For l-nordeprenyl, K(m1) and K(m2) were 0.96 +/- 0.05 and 168 +/- 15 micro M, and V(max1) and V(max2) 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 micro M 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 micro M 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.
Dragoni
S
S
Istituto di Scienze Farmacologiche, Centro Interdipartimentale di Ricerca sul Metabolismo dei Farmaci Neuropsicotropi, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
Bellik
L
L
Frosini
M
M
Sgaragli
G
G
Marini
S
S
Gervasi
P G
PG
Valoti
M
M
D000818:Animals; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D012642:Selegiline / Q000378:metabolism*
D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases