Indole‐N‐Methylation of β‐Carbolines: The Brain's Bioactivation Route to Toxins in Parkinson's Disease?a,b

Collins, Michael A.; Neafsey, Edward J.; Matsubara, Kazuo; Cobuzzi, Robert J.; Albores, Rudolph; Fields, Jeremy Z.; Rollema, Hans

doi:10.1111/j.1749-6632.1992.tb24551.x

Cited by 15 publications

(6 citation statements)

References 7 publications

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“…The etiology of PD is unknown, but a number of causative factors have been proposed, including mitochondrial impairments, oxidative stress (Mizuno et al 1987; Halliwell 1992), environmental neurotoxins such as paraquat and manganese, and endogenous toxic substances that have a similar structure to 1-methyl-4-phenyl-tetrahydropyridine (MPTP), such as methyl β-carboline and N-methylsalsolinol. (Collins et al 1992; Maruyama et al 1997; Naoi et al 2000). Excessive methylation might be involved in the pathogenesis of some cases of PD because injection of S-adenosyl methionine (SAM) into the rat brain induces PD-like behavioral, biochemical, and histological changes (Charlton and Way 1978; Crowell et al 1993; Charlton and Mack 1994).…”

Section: Introductionmentioning

confidence: 99%

Excessive S-adenosyl-l-methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: Possible role in S-adenosyl-l-methionine-induced Parkinson's disease-like disorders

et al. 2008

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Aims-Excessive methylation may be a precipitating factor for Parkinson's disease (PD) since Sadenosylmethionine (SAM), the endogenous methyl donor, induces PD-like changes when injected into the rat brain. The hydrolysis of the methyl ester bond of the methylated proteins produces methanol. Since methanol is oxidized into formaldehyde, and formaldehyde into formic acid in the body, we investigated the effects of SAM on the production of methanol, formaldehyde and formic acid in rat brain striatal homogenates and the toxicity of these products in PC12 cells.Main methods-radio-enzymatic and colorimetric assays, cell viability, Western blot. homogenates, respectively. SAM also significantly generated formaldehyde and formic acid in striatal homogenates. Formaldehyde was the most toxic metabolite to differentiated PC12 pheochromocytoma cells in cell culture studies, indicating that formaldehyde formed endogenously may contribute to neuronal damage in excessive methylation conditions. Subtoxic concentration of formaldehyde decreased the expression of tyrosine hydroxylase, the limiting factor in dopamine synthesis. Formaldehyde was more toxic to catecholaminergic PC12 cells than C6 glioma cells, indicating that neurons are more vulnerable to formaldehyde than glia cells.Significance-We suggest that excessive carboxylmethylation of proteins might be involved in the SAM-induced PD-like changes and in the aging process via the toxic effects of formaldehyde.

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Section: Introductionmentioning

confidence: 99%

Excessive S-adenosyl-l-methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: Possible role in S-adenosyl-l-methionine-induced Parkinson's disease-like disorders

et al. 2008

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“…Therefore, O-demethylation of these ␤-carbolines may be an important detoxication process protecting neurons against chemical damage. Moreover, such O-demethylation detoxication reactions may compete with the toxifying reactions of N-methylation that are thought to lead to intermediates that may trigger Parkinson's disease (Collins and Neafsey, 1985;Collins et al, 1992;de Meester, 1995;Aoyama et al, 2000;Gearhart et al, 2000Gearhart et al, , 2002.…”

Section: Substrate Hlm Metabolitementioning

confidence: 99%

“…Tryptophan-derived ␤-carbolines are similar to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in structure, which is known to induce immediate and irreversible parkinsonism through its neurotoxic metabolite, a quaternary ion (MPP ϩ ). Various studies indicate that the 2,9-di-N-methylated ␤-carboline cations, which are neurotoxic compared with MPP ϩ , also induce mitochondrial energy depletion and oxidative stress in nigrostriatum (Collins and Neafsey, 1985;Collins et al, 1987Collins et al, , 1992Collins, 2002). Moreover, the bioactivated, potentially neurotoxic N-methylated ␤-carbolinium ions are reported to be present in human brain (Matsubara et al, 1993).…”

mentioning

confidence: 99%

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Idle²,

Krausz

et al. 2003

J Pharmacol Exp Ther

113

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The psychotropic ␤-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K cat (min Ϫ1 ) and K m (M) values for harmaline were: CYP1A1, 10. 8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.The ␤-carboline alkaloids are present in plants and have been of interest due to their psychotropic properties (Picada et al., 1997). They may be formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with simple aldehydes or with pyruvic acid in mammals, including humans (Airaksinen and Kari, 1981;Melchior and Collins, 1982). Moreover, certain ␤-carbolines, such as pinoline, tryptoline, 6-hydroxy-tetrahydro-␤-carboline, harman, and norharman (Table 1), have been reported as normal constituents of human tissues and body fluids. Their levels in humans are usually elevated after drinking alcohol. The association of ␤-carbolines with alcohol dependence and brain damage has been suggested (Melchior and Collins, 1982;Collins, 2002).Endogenous and exogenous ␤-carboline alkaloids were reported to exert a wide spectrum of psychopharmacological and behavioral effects in the brain (Airaksinen and Kari, 1981). Most ␤-carbolines are strong reversible inhibitors of monoamine oxidase (MAO). Among them, harmaline and harmine (Table 1) exhibit the most potent inhibition toward purified MAO-A activity (Kim et al., 1997), and these are the principal active agents in Peganum harmala, a plant that has been used in traditional medicine for two millennia (Lamchou...

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“…In addition, cellular studies showed that TIQs exert a direct toxicity to dopaminergic neurons through inhibition of complex I enzymes, a mitochondrial mechanism similar to that of MPTP or rotenone exposure 54, 55. A similar cytotoxic mechanism has been reported as a consequence of the administration of beta‐carbolines, which have been hypothesized as a possible cause of PD 56–61. This further suggests that environmental factors may be relevant for developing PSP.…”

Section: Etiopathogenesismentioning

confidence: 81%

Update on epidemiological aspects of progressive supranuclear palsy

Litvan

2003

Mov Disord.

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The cause of progressive supranuclear palsy (PSP), the most common form of the atypical parkinsonian disorders, is unknown. PSP is characterized by four-repeat tau aggregates in neurons (neurofibrillary tangles) and glia in specific basal ganglia and brainstem areas. A thorough literature review led us to hypothesize that genetic and/or environmental factors contribute to its development. It is likely that inheritance of the H1/H1 tau genotype represents a predisposition to develop PSP requiring other environmental or genetic factors. Less likely, a relatively rare mutation with low penetrance could contribute to the abnormal tau aggregation present in this disorder. The possible role of chemicals in the diet or occupation, hypertension, traumatic brain injury, coffee, and inflammation or oxidative injury are reviewed.

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Indole‐N‐Methylation of β‐Carbolines: The Brain's Bioactivation Route to Toxins in Parkinson's Disease?^a,^b

Cited by 15 publications

References 7 publications

Excessive S-adenosyl-l-methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: Possible role in S-adenosyl-l-methionine-induced Parkinson's disease-like disorders

Excessive S-adenosyl-l-methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: Possible role in S-adenosyl-l-methionine-induced Parkinson's disease-like disorders

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Update on epidemiological aspects of progressive supranuclear palsy

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