Cytochrome P450-dependent n-dealkylation of l-deprenyl in C57BL mouse liver microsomes: effects of in vivo pretreatment with ethanol, phenobarbital, β-naphthoflavone and l-deprenyl

Abstract

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 β-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.