1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4--implications for susceptibility to Parkinson's disease.

摘要: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson-like syndrome through biotransformation by monoamine oxidase B to the neurotoxic metabolite 1-methyl-4-phenylpyridine. Neuroprotection may be provided parallel N-demethylation and N-oxidation pathways mediated microsomal cytochrome P450 flavin monooxygenase systems, respectively. The aims of this study were characterise MPTP human liver microsomes over wide range concentrations, identify enzymes involved in reaction. kinetics (1 microM - 3 mM) from an extensive metabolizer with respect P4502D6 (CYP2D6) activity biphasic (apparent Km1 Km2 values = 48 2882 microM). high affinity was abolished presence quinidine microM) absent genotypically poor CYP2D6. Yeast containing heterologously expressed CYP2D6 N-demethylated (Km 39 microM), there correlation between quinidine-inhibitable (50 (0.7-91%, mean 44%, total activity) alpha-hydroxylation metoprolol 11 livers (rs 0.92; P < .001). At 50 MPTP, N-demethylase also inhibited furafylline (10 ketoconazole (2 (mean inhibition 13%, respectively; n livers). CYP1A2 Km 2246 microM. These findings indicate that CYP2D6, and, lesser extent CYP3A4, have role protecting against Parkinson's disease induced other potential environmental neurotoxins. data provide some biochemical support for proposition metabolizers are overrepresented populations patients, smokers (induced CYP1A2?) underrepresented.