title: Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease.
abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.
authors.affiliation: Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6046, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Bajpai
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Sangar
authors.forename: Shilpee
authors.initials: S
authors.lastname: Singh
authors.forename: Weigang
authors.initials: W
authors.lastname: Tang
authors.forename: Seema
authors.initials: S
authors.lastname: Bansal
authors.forename: Goutam
authors.initials: G
authors.lastname: Chowdhury
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.forename: Ji-Kang
authors.initials: JK
authors.lastname: Fang
authors.forename: Martha V
authors.initials: MV
authors.lastname: Martin
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Narayan G
authors.initials: NG
authors.lastname: Avadhani
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D015259:Dopamine Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000201:enzymology* / Q000473:pathology; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011802:Quinidine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D015259:Dopamine Agents; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019389:Cytochrome P-450 CYP2D6; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C486391:Dnm1l protein, mouse; D034281:Dynamins; D011802:Quinidine