Inhibition of the Formation of Tetrahydroisoquinoline Alkaloids in Brain Homogenates

Alivisatos, Spyridon G.A.; Ungar, Frieda; Callaghan, Owen; Levitt, LeRoy P.; Tabakoff, Boris

doi:10.1139/o73-005

Cited by 17 publications

(3 citation statements)

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“…The effectiveness of pargyline as an MAO inhibitor indicated that a DA metabolite was the modifying agent as opposed to DA or DA-quinone. As previously discussed, these agents (especially Cys and GSH) were thought to form thiohemiacetals or otherwise directly interact with DOPAL . However, inhibition of protein binding by AscH – sheds some doubt on this theory given that AscH – does not contain any nucleophiles.…”

Section: Discussionmentioning

confidence: 99%

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Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Anderson

Florang

Schamp

et al. 2016

Chem. Res. Toxicol.

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3,4-Dihydroxyphenylacetaldehyde (DOPAL) is an endogenously produced toxic aldehyde. It is a bifunctional electrophile implicated in the loss of dopaminergic cells concomitant with Parkinson’s disease and neurodegeneration. DOPAL is known to react with proteins and amino acids such as N-acetyl Lys; oxidation of the catechol moiety to the quinone of DOPAL increases this reactivity. Here we demonstrate the ability of the antioxidants N-acetylcysteine, glutathione, and ascorbic acid to mitigate the reactivity of DOPAL with proteins and amino acids in a dose-dependent fashion. Conversely, Trolox did not lessen the observed reactivity with proteins. Interestingly, use of tricine, a buffer and reducing agent, in these systems also decreased the reactivity of DOPAL with amines, yielding tricine-derived free radical species. Modification of amines with aldehydes typically involves Schiff base chemistry; however, the observance of free radicals suggests that an oxidative step is involved in the reaction of DOPAL with lysine. Furthermore, while Schiff base formation is usually optimal at pH 5, the reaction rate of DOPAL with N-acetyl Lys is negligible at pH 5 and is enhanced under basic conditions (e.g. pH 9). Conditions of high pH are also favorable for catechol auto-oxidation, known to occur for DOPAL. The antioxidant-mediated protection demonstrated here suggests that oxidative stress may impart cellular vulnerability to protein modification by DOPAL. Therefore, depleted antioxidants and increased levels of lipid peroxidation products, known to prevent detoxifying metabolism of DOPAL, may present a survival challenge to dopaminergic cells targeted in Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

“…As previously discussed, these agents (especially Cys and GSH) were thought to form thiohemiacetals or otherwise directly interact with DOPAL. 40 However, inhibition of protein binding by AscH − sheds some doubt on this theory given that AscH − does not contain any nucleophiles.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Anderson

Florang

Schamp

et al. 2016

Chem. Res. Toxicol.

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“…Such an explanation would not suffice for the high degree of methylation of TIQs on the original phydroxyl group. This is apparent from the knowledge that the pK& for SAL, a TIQ that results in >95% 7-0-methyl product isomer, is 8.60-or only 0.4 pH units less than the for DA (Alivisatos et al, 1973), a substrate that is apparently only m-0-methylated in the CNS (Origitano and Collins, 1980). The 7-0-methylation of TIQs in brain is best explained if we consider that COMT in its neuronal environment contains, as proposed by Creveling et al (1970) for purified hepatic COMT, a hydrophobic region (Hr) adjacent to or within the active site.…”

Section: A Collins and T C Origitanomentioning

confidence: 99%

Catecholamine‐Derived Tetrahydroisoquinolines: O‐Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Collins

Origitano

1983

Journal of Neurochemistry

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The metabolism of 6,7-dihydroxy (catecholic)-1,2,3,4-tetrahydroisoquinolines (TIQs) is of interest because the heterocyclic substances may form in mammals normally or during certain disease via condensations of catecholamines (CAs) with aldehydes or alpha-keto acids. With a specific capillary gas chromatography procedure and confirmatory liquid chromatographic assays, we have determined the structural isomers and relative amounts of mono-O-methylated (phenolic) TIQ metabolites in several rat brain regions 40 min following the acute intracerebroventricular injection of four structurally related catecholic TIQs. In sharp contrast with the established selective m-O-methylation of dopamine (DA) by catechol-O-methyltransferase in brain, the two simple TIQs derived from DA produced predominantly or even exclusively the metabolic isomer arising from methylation of the original p-hydroxyl group (7-O-methylation). In three catecholaminergic brain regions examined, the 7-O-methyl isomer was the only detectable phenolic metabolite of (+/-) salsolinol-1-carboxylic acid (a condensation product of DA and pyruvic acid) and, as first noted by Bail et al. (1980), constituted 95% of the two possible isomeric mono-O-methyl metabolites of (+/-) salsolinol (TIQ derivative of DA and acetaldehyde). Though less, the 7-O-methyl isomers still were a significant proportion (40-55%) of the two mono-O-methylated metabolites of (+/-) 4-hydroxy-desmethylsalsolinol (a TIQ derived from norepinephrine and formaldehyde), or of the DOPA/acetaldehyde-derived TIQ, (cis) salsolinol-3-carboxylic acid. In the time frame of the study, all four administered TIQs showed higher levels in hypothalamus than in striatum or hippocampus, with the two carboxylated alkaloids displaying the greatest differences.(ABSTRACT TRUNCATED AT 250 WORDS)

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Formation of Aberrant Neurotransmitters and Its Implication for Alcohol Addiction and Intoxication

Alivisatos

Arora

1975

Biochemical Pharmacology of Ethanol

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Inhibition of the Formation of Tetrahydroisoquinoline Alkaloids in Brain Homogenates

Cited by 17 publications

References 0 publications

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite

Catecholamine‐Derived Tetrahydroisoquinolines: O‐Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Formation of Aberrant Neurotransmitters and Its Implication for Alcohol Addiction and Intoxication

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