MPTP and MPTP analogs induced cell death in cultured rat hepatocytes involving the formation of pyridinium metabolites (original) (raw)
Related papers
Mechanism of the neurotoxicity of MPTP: An update
Febs Letters, 1990
This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1methyl-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.
Mechanism of the neurotoxicity of MPTP
FEBS Letters, 1990
This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1methyl-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.
Toxication of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and analogs by monoamine oxidase
Biochemical Pharmacology, 1990
MPTP (I-methyl-Cphenyl-1,2,3,6_tetrahydropyridine) elicits motor deficits similar to those observed in Parkinson's disease. Before exerting its neurotoxic action, MPTP must be activated by brain monoamine oxidase (MAO) to the neurotoxic metabolite MPP+ (l-methyl-4-phenylpyridinium). MPTP derivatives differ in their reactivity as MAO substrates and in their neurotoxicity. A structure-reactivity relationship study based on literature data was undertaken in order to determine the key features in the structure of MPTP and analogs that are responsible for the reactivity towards MAO. Thirty-three MPTP derivatives (including MPTP itself) were included in the study. To explain the reactivity towards MAO of the 33 MPTP analogs, different statistical methods (principal component analysis, multiple linear regression analysis) as well as the CoMFA (Comparative Molecular Field Analysis) approach, a new tool in structure-activity correlations, were used. Linear regression analysis failed to yield any predictive model, but suggested some trends. In contrast, the CoMFA approach was successful in correlating structural features and MAO reactivity. Coefficient contour maps showed where differences in the steric field (van der Waals' interactions) are most highly associated with differences in MAO reactivity. Several positive (in the orrhoand mera-position of the phenyl group) and negative (in the paru-position of the phenyl group; beyond the N-methyl group) interaction regions were identified. Some structural features of the MAO active site could be postulated. First, the N-methyl group has the ideal size and elicits ideal interactions within the MAO active pocket, while smaller or larger groups are less favorable; second, paru-substituent on the phenyl ring produce steric hindrances and are unfavorable to reactivity; third, orthoand meta-substituents may have stabilizing interactions within the active pocket and are favorable to the reactivity. Moreover the model derived by CoMFA allowed us to make succesful predictions of reactivity towards MAO for several additional tetrahydropyridines.
Toxicology, 1988
It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.
N-methyl-4-phenylpyridinium (MPP+) potentiates the killing of cultured hepatocytes by catecholamines
Chemico-Biological Interactions, 1993
The role of catecholamines in the toxicity of MPTP (N-methyl-4-pheny-1,2,3,6-tetrahydropyridine) was explored. The killing of cultured hepatocytes by dopamine and 6-hydroxydopamine was enhanced following inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), a manipulation known to sensitize such cells to an oxidative stress. The participation of activated oxygen species in the cell injury under such circumstances was shown by the ability of catalase and the ferric iron chelator deferoxamine to protect the hepatocytes. The toxicity of catecholamines was also potentiated by the mitochondrial site I (NADH dehydrogenase) inhibitor rotenone. MPP ÷ (N-methyl-4-phenylpyridinium), the putative toxic metabolite of MPTP is also a site I inhibitor. Incubation of hepatocytes with MPP + similarly potentiated the toxicity of 6hydroxydopamine, dopamine, and norepinephrine under conditions where MPP + alone or catecholamines alone did not kill cells. Hepatocytes that had accumulated dopamine from the medium were killed by a subsequent exposure to MPP + in the absence of a catecholamine in the medium. Hepatocytes that had not been pretreated with dopamine were not affected by the subsequent exposure to MPP +. These data indicated that catecholamines render hepatocytes more susceptible to the toxicity of MPP ÷ and suggest that the presence of catecholamines in specific neurons in the brain may be related to the selective neurotoxicity of MPTP.
Life sciences, 1985
l-methyl-4-phenylpyridine (MPP+), a major metabolite of the neurotoxin, l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP) inhibited the ADP-stimulated and uncoupled oxidation of NADHlinked substrates by brain mitochondrial preparations. MPTP itself was ineffective. The apparent Ki's for MPP + inhibition of pyruvate or glutamate oxidation by purified rat brain mitochondria were approximately 300 and 400 ~M, respectively; with mouse brain mitochondria the values were lower, 60 and 150~M, respectively. Succinate oxidation was unaffected by either compound. Compromise of mitochondrial oxidative capacity by MPP + could be an important factor in mechanisms underlying the toxicity of MPTP.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2001
Klein, Bradley, G., Michael L. Kirby, Ethan R. Freeborn and Jeffrey R. Bloomquist: Pharmacological Properties of the MPTP Analog Trans-l-methyl-4-[4-dimethylaminophenylethenyl]-l,2,3,6tetrahydropyridine and its Pyridinium Metabolite in Mouse Brain Synaptosomes: A Potential Visual Marker for Substrates of MPTP-Induced Neurotoxicity. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 2001, 25, pp. 591--608. ~2001 Elsevier Science Inc.
Journal of Neurochemistry, 1991
Single toxic doses of I -methyl-4-phenyl-I ,2,3,6tetrahydropyridine (MPTP) * HCI (2.5 mg/kg i.v.) and 4'amino-MPTP-2HC1(22.5 mg/kg) induce loss of stnatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'amino-MPTP, dose-response studies of these compounds were camed out in the dog, using 6-and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1 .O, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (1 5,7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA) were decreased in a doserelated fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measure-