Interactions of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidases

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates. The nigrostriatal toxicity is not due to MPTP itself but to one or more oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or 'suicide' process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme.

Mechanism of the neurotoxicity of MPTP

“…Slow non-enzymic oxidation by molecular 02 has also been observed. Both MAO A and B were shown [8] to oxidize MPDP ÷ and its analogs relatively slowly, the rate in each case being two orders of magnitude less than the values shown in Table I. In brain mitochondria the oxidation is sensitive to MAO B inhibitors, but it has been reported to be insensitive in hepatocytes [17], perhaps because of the The control substrates were kynuramine for MAO-A and benzylamine for MAO-B.…”

“…Early studies [8] indicated that the rate of inactivation of MAO B by MPTP and MPDP ÷ were identical, suggesting that processing of the latter compound was responsible for the irreversible loss of activity. Recent studies [26], using a rapid scan spectrophotometer and a multicomponent analysis program, confirmed that the mechanism-based inactivation of MAO B by the dihydropyridinium is faster than inactivation by the tetrahydropyridinium for MPTP and several analogs, whereas the reverse is true of MAO A, which processes MPDP ÷ and its analogs poorly.…”

“…The biochemical events which follow the passage of MPTP through the blood-brain barrier, as visualized in 1987, are summarized in Scheme I. The first step in the development of neurotoxicity is thus oxidation by MAO B in the astrocytes of the brain to the dihydropyridinium form (MPDP +), which is then further oxidized in part by this enzyme, in part nonenzymically to the pyridinium form, MPP + [8]. The MPP + is selectively taken up by the dopamine reuptake system at dopaminergic synapses and probably pumped into the stroma of the neurons [9].…”

Mitochondrial dysfunction in Parkinson's disease

“…MPTP is converted to 1-methyl 4-phenylpyridinium (MPP) via the intermediate 2,3-dihydropyridinium (MPDP) by monoamine oxidase (MAO) A and B, preferentially by MAO-B. 71 This conversion probably occurs in glia, as MAO-B is predominantly located in astrocytes and serotinergic neurons in the CNS where it is located on the mitochondrial outer membrane. 72 Inhibition of MAO can prevent MPTP toxicity.…”

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

“…Shortly thereafter we showed [2,3] (1) that not only MPTP, but also its primary oxidation product, MPDP+, are mechanism-based ('suicide') inhibitors of monoamine oxidases A and B, (2) that under the experimental conditions used the decay of activity on incubation of either enzyme with MPTP is exponential and is not reversed by gel exclusion or brief dialysis, but (3) that after prolonged dialysis of monoamine oxidase B previously inactivated by MPTP a part of the activity returns [3]. The mechanism-based inhibition of monoamine oxidases by MPTP and MPDP+ was readily distinguished from the reversible competitive inhibition of both monoamine oxidases by MPTP, MPDP+ and by MPP+, the fourelectron oxidation product: the A enzyme was found to be far more sensitive to reversible inhibition by MPDP+ and MPP+ than was the B form [2,3]. The partition coefficients (the rate of product generation divided by the rate of inactivation of the enzyme) for the inactivation were large, since the rate of oxidation of MPTP by either enzyme greatly exceeded the rate of inactivation.…”