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.
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.
Valoti
M
M
Istituto di Scienze Farmacologiche, Università degli Studi di Siena, via Piccolomini 170, 53100, Siena, Italy. valoti@unisi.it
Fusi
F
F
Frosini
M
M
Pessina
F
F
Tipton
K F
KF
Sgaragli
G P
GP
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D000077604:Fomepizole; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010634:Phenobarbital / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D012642:Selegiline / Q000378:metabolism* / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011720:Pyrazoles; D012642:Selegiline; D000431:Ethanol; D019324:beta-Naphthoflavone; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D007654:Ketoconazole; D004221:Disulfiram; D010634:Phenobarbital