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