Transformation of dopamine and .alpha.-methyldopamine by NG108-15 cells: formation of thiol adducts

Patel, Nita; Kumagai, Yoshito; Unger, S E; Fukuto, Jon M.; Cho, Arthur K.

doi:10.1021/tx00022a004

Cited by 43 publications

(23 citation statements)

References 8 publications

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“…33,34) Indeed, the reactivity of the thioether metabolites may exceed that of the parent polyphenol. In biological media, α-MeDA undergoes oxidation to the corresponding o-quinone, which is conjugated with GSH 26,35) to form 5-(GSH)-α-MeDA. This metabolite is readily oxidized to the o-quinone-GSH derivate, followed by subsequent addition of a second molecule of GSH to form 2,5-bis(glutathion-S-yl)-α-MeDA.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

Macedo

Branco

Ferreira

et al. 2007

JOURNAL OF HEALTH SCIENCE

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3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There are growing evidences that the MDMA neurotoxic profile may be highly dependent on its hepatic metabolism. MDMA metabolism leads to the production of highly reactive derivates, namely catechols, catechol thioethers, and quinones. In this study the electrochemical oxidation-reduction processes of MDMA human metabolites, obtained by chemical synthesis, were evaluated by cyclic voltammetry based on an electrochemical cell with a glassy carbon working electrode. The toxicity of α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA] to rat cortical neurons was then correlated with their redox potential. The obtained data demonstrated that the lower oxidation potential observed for the catecholic thioether of α-MeDA correlated with the higher toxicity of this adduct. This accounts for the use of voltammetry data in predicting the toxicity of MDMA metabolites.

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Section: Discussionmentioning

confidence: 99%

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

Macedo

Branco

Ferreira

et al. 2007

JOURNAL OF HEALTH SCIENCE

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“…The catecholamine metabolites are very unstable and are either conjugated with sulfate/gluc-uronic acid or O-methylated to 3-O-methyl-N-Me-␣-MeDA or 3-O-methyl-␣-MeDA in reactions catalyzed by catechol Omethyl-transferase. Alternatively, because N-Me-␣-MeDA and ␣-MeDA are both catechols, they can rapidly undergo oxidation to the corresponding ortho-quinones, which are highly electrophilic, as evidenced by their ability to react readily with the cysteinyl sulfhydryl group in glutathione (GSH) to form GSH conjugates (Hiramatsu et al, 1990;Patel et al, 1991) (Fig. 1).…”

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confidence: 99%

Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

Erives¹,

Lau²,

Monks³

2007

J Pharmacol Exp Ther

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The serotonergic neurotoxicity of 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-␣-methyldopamine (N-Me-␣-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-␣-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. The serotonergic neurotoxicity 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-(Ϯ)-methylenedioxyamphetamine (MDA) is dependent on the route of administration (O'Shea et al., 1998). Direct injection of MDMA and MDA into the brain fails to reproduce the acute or long-term neurotoxic effects evident following peripheral administration of these drugs (Schmidt et al., 1987;Paris and Cunningham, 1992), suggesting that systemic (liver) metabolism contributes to the neurotoxicity of MDMA and MDA. Indeed, although MDMA targets the serotonergic system in humans, nonhuman primates, and rats, the finding that MDMA does not affect the serotonergic system in mice but rather targets the dopaminergic system has been attributed to metabolic differences between species (Logan et al., 1988;Escobedo et al., 2005). Perhaps the most convincing evidence that peripheral metabolism of MDMA is required for neurotoxicity was provided by the work of Esteban et al. (2001). In this study, MDMA was perfused into the hippocampus in amounts sufficient to give rise to the range of concentrations observed following peripheral administration of neurotoxic doses of MDMA. After perfusion, acute monoamine release was observed in the absence of long term depletions in 5-HT levels. These data are consistent with the hypothesis that peripheral generation of neurotoxic metabolites contributes to MDMA-induced serotonergic neurotoxicity.MDMA is N-demethylated to MDA and O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) (Fig. 1) (Lin et al., 1992). N-Demethylation in humans is a minor metabolic pathway (ϳ10%), but ␣-MeDA is a metabolite of both MDMA and MDA. Isoenzymes belonging to the CYP2D subfamily, and the CYP2B or CYP3A1 isoforms, catalyze the low-and high-K m O-demethylenation reactions, respectively (de la Torre et al., 2004). The catecholamine metabolites are very unstable and are either conjugated with sulfate/glucArticle, publication date, and citation information can be found at

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“…injection (McCann and Ricaurte, 1991;Elayan et al, 1992;Johnson et al, 1992;Zhao et al, 1992). ␣-MeDA and N-Me-␣-MeDA are catechols that can undergo oxidation to the corresponding ortho-quinones, which are highly electrophilic, as evidenced by their ability to react readily with the cysteinyl sulfhydryl group in GSH to form GSH conjugates (Hiramatsu et al, 1990;Patel et al, 1991). Quinol-thioethers retain the ability to redox cycle and produce reactive oxygen species and arylate tissue macromolecules .…”

mentioning

confidence: 99%

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

Jones¹,

Duvauchelle²,

Ikegami³

et al. 2005

J Pharmacol Exp Ther

111

130

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The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell ␥-glutamyl transpeptidase (␥-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of ␣-methyl dopamine (␣-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of ␥-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-␣-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-␣-MeDA (and ␣-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.Although the selectivity of (Ϯ)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and (Ϯ)-3,4-methylenedioxyamphetamine (MDA) for the serotonergic system in rats and humans is firmly established, the mechanism(s) involved are not fully understood. In rats, MDMA is cleared mainly by hepatic metabolism by N-demethylation to form MDA. MDMA and MDA are further O-demethylenated to 3,4-dihydroxymethamphetamine (N-methyl-␣-methyldopamine; N-Me-␣-MeDA) and 3,4-dihydroxyamphetamine (␣-methyldopamine; ␣-MeDA), respectively. N-Me-␣-MeDA and ␣-MeDA are highly redox-unstable catechols and are conjugated with sulfate and glucuronic acid. Both catechols can also be rapidly oxidized to their corresponding orthoquinones and form adducts with glutathione (GSH) and other thiol-containing compounds (Lim and Foltz, 1988;Hiramatsu et al., 1990). Alternatively, N-Me-␣-MeDA and ␣-MeDA can be O-methylated to form 4-hydroxy-3-methoxymethamphetamine (3-O-Me-N-Me-␣-MeDA) or 4-hydroxy-3-methoxyamphetamine (3-O-Me-␣-MeDA), respectively.

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Transformation of dopamine and .alpha.-methyldopamine by NG108-15 cells: formation of thiol adducts

Cited by 43 publications

References 8 publications

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

Serotonergic Neurotoxic Metabolites of Ecstasy Identified in Rat Brain

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