Identification of the major transport pathway for the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium

Dunigan, Cheryl D.; Shamoo, Adil E.

doi:10.1016/0306-4522(96)00266-7

Cited by 16 publications

(7 citation statements)

References 24 publications

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“…MPP + , the active metabolite produced by monoamine oxidase‐B‐catalyzed oxidation of MPTP in the brain, enters dopaminergic neurons via the dopamine transporter, is concentrated in the mitochondria, and impairs mitochondrial respiration by inhibition of mitochondrial complex I and depletion of adenosine triphosphate. Mitochondrial energy depletion generates ROS, which, in turn, leads to dopaminergic cell death (Dunigan and Shamoo, 1996). PC12, SH‐N‐5Y5, and other cell lines have been successfully used as MPP + ‐induced acute cell PD models (Offen et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease

Cai

Jia

Liu

et al. 2008

J of Neuroscience Research

141

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To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 enzyme inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity.

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Section: Discussionmentioning

confidence: 99%

Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease

Cai

Jia

Liu

et al. 2008

J of Neuroscience Research

141

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“…In the case of 81, the intermediate 2, 3-dihydropyridinium species MPDP + (82), derived from the MAO-B mediated bioactivation in the brain, undergoes a further two electron oxidation to the corresponding pyridinium species MPP + (83) [99][100][101]. Pyridinium 83 is actively transported into dopaminergic nerve terminals by the dopamine uptake system where it localizes in the mitochondrial matrix and inhibit complex I of the mitochondrial electron transport chain leading to cessation of oxidative phosphorylation and ATP depletion [102][103][104][105]. Interestingly, 82 is an excellent substrate for hepatic aldehyde oxidase that catalyzes its detoxification to the lactam 84 [106].…”

Section: Occurrence Frequency and Mechanismmentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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“…The selective toxicity of MPTP is remarkable since the target nigrostriatal neurons do not catalyze the bioactivation reaction (53) presumably because they lack MAO-B activity (54)(55)(56). This dilemma appears to have been resolved by the demonstration that MPP + is concentrated in the dopaminergic nigrostriatal nerve terminals via the dopamine transporter (57,58). On the other hand, the selective toxicity of MPP + on nigrostriatal dopaminergic pathways is not reflected in differences in striatal vs mesolimbic transporters (59) or vesicular transporters in the sensitive C57BL/6 mouse compared to the insensitive CD1 mouse (60).…”

Section: T H Imentioning

confidence: 99%

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

Castagnoli

Rimoldi

Bloomquist

et al. 1997

Chem. Res. Toxicol.

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A major theme explored in this review is the MAO-and cytochrome P450-catalyzed alpha-carbon oxidations of selected cyclic tertiary amines to give iminium metabolites that undergo further chemical modifications to form known or potentially toxic products. The most dramatic illustration of this type of bioactivation process is the conversion of the parkinsonian-inducing neurotoxin MPTP (23) by brain MAO-B to the iminium (dihydropyridinium) metabolite 24 which is oxidized further to the pyridinium species MPP+ (25). The selective destruction of nigrostriatal neurons by MPP+ is dependent on a unique sequence of events (transport into the nerve terminals by the dopamine transporter, localization in the inner mitochondrial membrane by electromotive forces, and inhibition of complex I of the mitochondrial electron transport chain) that, fortunately, are unlikely to be encountered with many substances. A second example of a well-documented metabolic bioactivation sequence involves the highly toxic pyrrolizidine alkaloids (102). These compounds undergo cytochrome P450-catalyzed alpha-carbon oxidation which converts the 3-pyrrolinyl moiety present in the parent alkaloids into a pyrrolyl-containing metabolite (105). The presence of labile functional groups results in the spontaneous conversion of 105 to reactive electrophilic products (106 and 108) that undergo Michael addition reactions with nucleophiles on biomacromolecules leading to a variety of toxic outcomes. Less clearly defined are the potential contributions to neurodegenerative processes that may be mediated by low-level, long term exposure to less potent toxins. Examples of potential proneurotoxins are the endogenously formed tetrahydroisoquinolines (such as40-50) and tetrahydro-beta-carbolines (such as 54) that may be biotransformed to neurotoxic isoquinolinium (such as 51) and beta-carbolinium (such as 52) species in the brain. A similar argument can be made for 4-piperidinols (compounds that are at the same oxidation state as the tetrahydropyridines) which may be metabolized via iminium intermediates to amino enols that spontaneously convert to dihydropyridinium species and hence to pyridinium metabolites (67-->68-->69-->70-->71, Scheme 10). This type of reaction sequence has been well documented with the parkinsonian-inducing neuroleptic agent haloperidol (72) which is metabolized in humans, baboons, and rodents to the pyridinium species HPP+ (75), a potent inhibitor of mitochondrial respiration. Finally, an appreciation of the alpha-carbon oxidations of fully reduced azacycles such as (S)-nicotine (61) and phencyclidine (82) to chemically reactive metabolites that form covalent adducts with proteins, including the enzymes that are responsible for their formation, may prove of toxicological importance when attempting to account for the effects of chronic abuse of these potent drugs.1

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Identification of the major transport pathway for the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium

Cited by 16 publications

References 24 publications

Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease

Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

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Identification of the major transport pathway for the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium

Cited by 16 publications

References 24 publications

Polyhydroxylated fullerene derivative C60(OH)24 prevents mitochondrial dysfunction and oxidative damage in an MPP+‐induced cellular model of Parkinson's disease

Polyhydroxylated fullerene derivative C60(OH)24 prevents mitochondrial dysfunction and oxidative damage in an MPP+‐induced cellular model of Parkinson's disease

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Potential Metabolic Bioactivation Pathways Involving Cyclic Tertiary Amines and Azaarenes

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Product

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Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease

Polyhydroxylated fullerene derivative C₆₀(OH)₂₄ prevents mitochondrial dysfunction and oxidative damage in an MPP⁺‐induced cellular model of Parkinson's disease