Metabolism of the neurotoxin in MPTP by human liver monoamine oxidase B

Fritz, Richard R.; Abell, Creed W.; Patel, Nutan T.; Gessner, Wieslaw; Brossi, Arnold

doi:10.1016/0014-5793(85)80713-4

Cited by 72 publications

(43 citation statements)

References 18 publications

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“…With respect to the subtypes of the enzyme, it was shown that MPP+ potently and competitively inhibits MAO-A, which therefore does not significantly contribute to the conversion of MPTP to MPP +. The B form of the enzyme which appears to be only slightly inhibited by MPP + (Fritz et al, 1985), plays the predominant role in the bioactivation of MPTP (Singer et al, 1987). However, in the light of the present findings, i.e.…”

Section: Discussioncontrasting

confidence: 51%

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Feuerstein

Hedler

Jackisch

et al. 1988

British J Pharmacology

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1 Slices of rabbit caudate nucleus were preincubated for up to 24h in vitro in the presence of the neurotoxic compound 1-methyl-4-phenyl-pyridinium (MPP+). Subsequently the levels of endogenous monoamines in the slices were determined by h.p.l.c. with electrochemical detection. MPP +, in concentrations higher than 32 nm significantly diminished the dopamine levels within the slices in a concentration-and time-dependent manner; at 32yM the depletion was more than 95%. The concentration of the major metabolite of dopamine, dihydroxyphenyl acetic acid (DOPAC) was decreased at concentrations of MPP+ that did not alter dopamine levels. Thus, MPP+ increased the dopamine/DOPAC ratio. 2 In contrast, both 5-hydroxytryptamine (5-HT) levels and 5-HT/5-hydroxyindolacetic acid (5-HIAA) ratios were increased at nanomolar concentrations of MPP +. 5-HT was significantly reduced only at 32 pM.3 The dopamine uptake inhibitor nomifensine reduced the depletory effect of MPP + on dopamine and DOPAC content. 4 Following 24 h pretreatment with MPP +, the uptake of [3H]-dopamine into rabbit caudate nucleus slices was either enhanced (at 0.32 pM, 1 pM and 3.2 pM MPP +) or reduced (at 32 JM MPP+).5 Preincubation of slices with 1OpM MPP + for only 1 h increased their 3H-labelling (in contrast to 24 h pretreatment) whereas after 9 h no net increase was detectable. After 1 and 9 h MPP + pretreatment, much less deaminated metabolites of [3H]-dopamine were found in the incubation medium of MPP+ treated slices than in the medium of control slices. These findings suggest that MPP + strongly inhibits the enzyme monoamine oxidase (MAO) within dopaminergic (and 5-hydroxytryptaminergic) (Snyder & D'Amato, 1986). In favour of the role of the substantia nigra in the pathogenesis it was assumed that within pigmented cell bodies of nigral neurones MPP+ was bound to neuromelanin and gradually released in a depot-like fashion, maintaining a toxic intracellular concentration of MPP +. However, since monoamine uptake is more prominent in nerve endings than in cell bodies (Snyder & D'Amato, 1986), the dopaminergic terminal field in the striatum rather than the cell bodies of the substantia nigra could be a primary target for MPP + toxicity.In the present investigation we studied the effects of long term incubation with MPP+ in caudate tissue of the rabbit in vitro in order to establish clear concentration-effect relationships and to provide a more accessible and less expensive experimental model than that of MPTP-induced Parkinsonism in primates in vivo. Acute dopamine releasing effects of MPTP and of MPP + in rat CNS tissue have already been described (Schmidt et al., 1984;Markstein & Lahaye, 1985;Rollema et al., 1986a). However, acute effects may not reflect adequately the toxic effects of MPP + on the dopaminergic system in vivo since, ultimately, the destruction of dopaminergic cells leads to MPTP-induced Parkinsonism.The analysis of subacute effects of MPTP or MPP + on cultured neuronal cells (Mytilineou & Cohen, 1984) Ci mmol-1) in a volume of 4ml...

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Section: Discussioncontrasting

confidence: 51%

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Feuerstein

Hedler

Jackisch

et al. 1988

British J Pharmacology

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“…The reason why they failed to observe that the A enzyme is subject to both reversible (competitive) and irreversible (non-competitive) effects may have been due to the experimental conditions used by these workers, including the radiochemical assay based on a single time point. In contrast, Fritz et al [5] and Brossi et al [6], using appropriate spectrophotometric assays, confirmed the reports [1][2][3] that monoamine oxidase B undergoes mechanism-based inhibition by MPTP and MPDP+, but, curiously, claimed that MPP+ also produces time-dependent irreversible inactivation of monoamine oxidase B [5]. This is quite unlikely, since MPP+ cannot undergo further oxidation by this enzyme; moreover, the previous data contradict it [2,3].…”

Section: Introductionmentioning

confidence: 79%

“…Arai et al [7,8], also reported that MPTP is a 'suicide substrate' (i.e., mechanism-based inhibitor) of monoamine oxidase B. They also observed inactivation by 4-phenyltetrahydropyridine, in conflict with the earlier report of Fritz et al [5], who found no inhibition by 4-phenyltetrahydropyridine, a discrepancy probably again due to the assay procedure used by the Japanese workers [7,8], which may yield misleading kinetic data. Using appropriate initial-rate measurements, our findings were confirmed and significantly extended by Tipton et al [9].…”

Section: Introductionmentioning

confidence: 91%

“…Thus the monophasic nature of logarithmic plots of the decrease in activity with time observed by several workers [3][4][5] and the similarity of the pseudo-first-order rate constants from the inactivation of monoamine oxidase B by MPTP and MPDP+ [2] have precluded the drawing of conclusions as to whether inactivation of the enzyme occurs during the first or the second two-electron transfer from MPTP or both. Later, the present authors found that, by varying the concentrations of MPTP or of other tetrahydropyridines and of the enzyme, biphasic kinetics become apparent.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines

Krueger

McKeown

Ramsay

et al. 1990

Biochemical Journal

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I-Methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) and its primary oxidation product, l-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), are mechanism-based inhibitors of monoamine oxidases A and B. The pseudo-first-order rate constants for inactivation were determined for various analogues of MPTP and MPDP+ and the concentrations in all redox states were measured throughout the reaction. Disproportionation was observed for all the dihydropyridiniums, but non-enzymic oxidation was insignificant. The dihydropyridiniums were poor substrates for monoamine oxidase A and, consequently, inactivated the enzyme only slowly, despite partition coefficients lower than those for the tetrahydropyridines. For monoamine oxidase B, the dihydropyridiniums were more effective inactivators than the tetrahydropyridines. Substitutions in the aromatic ring had no major effect on the inactivation of monoamine oxidase B, but the 2'-ethyl-and 3'-chloro-substituted compounds were very poor mechanism-based inactivators of monoamine oxidase A. It is clear that both oxidation steps can generate the reactive species responsible for inactivation.

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“…Several laboratories have studied the oxidation of synthetic analogs of MPTP [18][19][20]. As seen in Table I, 2' -methyl-MPTP, 2' -C1-MPTP, 3' -C1-MPTP, and 1-methyl-4-benzyl-tetrahydropyridine are all better substrates of MAO B than benzylamine, previously the best substrate known.…”

Section: Contributions To the Biochemistry Of Monoamine Oxidasesmentioning

confidence: 99%

Mechanism of the neurotoxicity of MPTP

1990

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This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

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Metabolism of the neurotoxin in MPTP by human liver monoamine oxidase B

Abstract: The neurotoxm I-methyl-4-phenyl-1,2,3,6-tetrahydropyrldlne (MPTP)

Cited by 72 publications

References 18 publications

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines

Mechanism of the neurotoxicity of MPTP

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