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 Par kinson's disease. It appears to exert this action independently of its inhi bition of monoamine oxidase B (MAO-B) and some of its metabolites are thoug ht to contribute. Cytochrome P450 (CYP) activities are known to give rise t o L-deprenyl metabolites that may affect the dopaminergic system. In order to clarify the interactions of L-deprenyl with these enzymes, C57BL mice we re treated with L-deprenyl, ethanol, phenobarbital or beta-naphthoflavone t o induce different CYP isozymes. After preincubation of L-deprenyl with liv er microsomes from control or treated mice, the metabolites were analysed b y a GLC method. L-deprenyl(10 mg/kg i.p. for 3 days) caused a significant d ecrease in total CYP levels (0.315 +/- 0.019, L-deprenyl; 0.786 +/- 0.124, control, nmol/mg protein) and CYP2E1-associated p-nitrophenol hydroxylase a ctivity (0.92 +/- 0.04 vs. 1.17 +/- 0.06 nmol/min/mg). Both phenobarbital a nd 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/m g). Moreover, the N-dealkylation pathways of deprenyl are inhibited by 4-me thylpyrazole and disulfiram, two CYP2E1 inhibitors. None of the other treat ments modified L-deprenyl metabolism. These findings indicate that mainly C YP2E1 and to a lesser extent CYP2B isozymes are involved in L-deprenyl meta bolism. They also suggest that, by reducing CYP content, L-deprenyl treatme nt may impair the metabolic disposition of other drugs given in combination regimens. (C) 2000 Elsevier Science B.V. All rights reserved.