Document Detail


Cytochrome P450-dependent N-dealkylation of L-deprenyl in C57BL mouse liver microsomes: effects of in vivo pretreatment with ethanol, phenobarbital, beta-naphthoflavone and L-deprenyl.
MedLine Citation:
PMID:  10729359     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The monoamine oxidase inhibitor L-deprenyl [(-)-deprenyl, selegiline] is an effective therapeutic agent for improving early symptoms of idiopathic Parkinson's disease. It appears to exert this action independently of its inhibition of monoamine oxidase B (MAO-B) and some of its metabolites are thought to contribute. Cytochrome P450 (CYP) activities are known to give rise to L-deprenyl metabolites that may affect the dopaminergic system. In order to clarify the interactions of L-deprenyl with these enzymes, C57BL mice were treated with L-deprenyl, ethanol, phenobarbital or beta-naphthoflavone to induce different CYP isozymes. After preincubation of L-deprenyl with liver microsomes from control or treated mice, the metabolites were analysed by a GLC method. L-deprenyl (10 mg/kg i.p. for 3 days) caused a significant decrease in total CYP levels (0.315+/-0.019, L-deprenyl; 0.786+/-0.124, control, nmol/mg protein) and CYP2E1-associated p-nitrophenol hydroxylase activity (0.92+/-0.04 vs. 1.17+/-0.06 nmol/min/mg). Both phenobarbital and ethanol increased the N-depropynylation activity towards L-deprenyl that leads to the formation of methamphetamine (4. 11+/-0.64, phenobarbital; 4.77+/-1.15, ethanol; 1.77+/-0.34, control, nmol/min/mg). Ethanol alone increased the N-demethylation rate of L-deprenyl, that results in formation of nordeprenyl (3.99+/-0.68, ethanol; 1.41+/-0.31, control, nmol/min/mg). Moreover, the N-dealkylation pathways of deprenyl are inhibited by 4-methylpyrazole and disulfiram, two CYP2E1 inhibitors. None of the other treatments modified L-deprenyl metabolism. These findings indicate that mainly CYP2E1 and to a lesser extent CYP2B isozymes are involved in L-deprenyl metabolism. They also suggest that, by reducing CYP content, L-deprenyl treatment may impair the metabolic disposition of other drugs given in combination regimens.
Authors:
M Valoti; F Fusi; M Frosini; F Pessina; K F Tipton; G P Sgaragli
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of pharmacology     Volume:  391     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-04-21     Completed Date:  2000-04-21     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  199-206     Citation Subset:  IM    
Affiliation:
Istituto di Scienze Farmacologiche, Università degli Studi di Siena, via Piccolomini 170, 53100, Siena, Italy. valoti@unisi.it
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MeSH Terms
Descriptor/Qualifier:
Animals
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  biosynthesis,  metabolism*
Disulfiram / pharmacology
Enzyme Induction
Enzyme Inhibitors / pharmacology
Ethanol / pharmacology*
Isoenzymes / antagonists & inhibitors,  biosynthesis,  metabolism
Ketoconazole / pharmacology
Mice
Mice, Inbred C57BL
Microsomes, Liver / enzymology,  metabolism*
Monoamine Oxidase Inhibitors / metabolism*
NADH, NADPH Oxidoreductases / metabolism
NADPH-Ferrihemoprotein Reductase
Phenobarbital / pharmacology*
Pyrazoles / pharmacology
Selegiline / metabolism*,  pharmacology
beta-Naphthoflavone / pharmacology*
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Isoenzymes; 0/Monoamine Oxidase Inhibitors; 0/Pyrazoles; 14611-51-9/Selegiline; 50-06-6/Phenobarbital; 6051-87-2/beta-Naphthoflavone; 64-17-5/Ethanol; 65277-42-1/Ketoconazole; 7554-65-6/fomepizole; 9035-51-2/Cytochrome P-450 Enzyme System; 97-77-8/Disulfiram; EC 1.6.-/NADH, NADPH Oxidoreductases; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase

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