Cytochrome P450-dependent metabolism of l-deprenyl in monkey (Cercopithecus aethiops) and C57BL/6 mouse brain microsomal preparations.
The aim of the present investigation was to characterize the cytochrome P450 (CYP)-dependent metabolism of l-deprenyl by brain microsomal preparations obtained from two different animal models that have been extensively used in Parkinson's disease studies, namely monkey (Cercopithecus aethiops) and C57BL/6 mouse. In monkey brain microsomal fractions, the apparent Km values for methamphetamine formation from l-deprenyl were 67.8 +/- 1.0 and 72.0 +/- 1.6 microm, in the cortex and striatum, respectively. Similarly, for nordeprenyl formation from l-deprenyl, Km values in cortex and striatum were 21.3 +/- 3.2 and 27.3 +/- 4.0 microm, respectively. Both metabolic pathways appear to be more efficient in the cortex than in the striatum as the Vmax for microsomal preparation was lower in the striatum for the formation of both metabolites. The formation rate of l-methamphetamine was up to one order of magnitude greater than that of nordeprenyl. Inhibition analysis of both pathways in monkey brain suggested that l-methamphetamine formation is catalysed by CYP2A and CYP3A, whereas only CYP3A appears to be involved in nordeprenyl formation. With microsomal preparations from whole brain of C57BL/6 mice, the only l-deprenyl metabolite that could be detected was methamphetamine and the Km and Vmax values were similar to those determined in monkey cortex (53.6 +/- 2.9 microm and 33.9 +/- 0.4 pmol/min/mg protein, respectively). 4-Methylpyrazole selectively inhibited methamphetamine formation, suggesting the involvement of CYP2E1. In conclusion, the present study indicates that l-deprenyl is effectively metabolised by CYP-dependent oxidases in the brain, giving rise mainly to the formation of methamphetamine, which has been suggested to play a role in the pharmacological effects of the parent drug. The results also demonstrate that there are differences between species in CYP-dependent metabolism of l-deprenyl.
Dragoni
Stefania
S
Istituto di Scienze Farmacologiche, Centro Interdipartimentale di Ricerca sul Metabolismo dei Farmaci Neuropsicotropi, Università di Siena, Siena, Italy.
Bellik
Lydia
L
Frosini
Maria
M
Matteucci
Giacomo
G
Sgaragli
Giampietro
G
Valoti
Massimo
M
D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D012642:Selegiline / Q000378:metabolism* / Q000493:pharmacokinetics; D013045:Species Specificity
D000978:Antiparkinson Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D012642:Selegiline; D003577:Cytochrome P-450 Enzyme System