2003
DOI: 10.1016/s0006-8993(03)03319-5
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Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy)

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Cited by 28 publications
(20 citation statements)
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“…P450-mediated oxidation of the methylene carbon in both compounds would lead to formation of unstable intermediates, which are then demethylenated to catechols (3,4-dihydroxymethamphetamine and ␣-methyldopamine) or dehydrated to carbenes. The former compounds may be oxidized further to orthoquinones, which can react with nucleophilic groups on macromolecules or conjugate with glutathione to form neurotoxins (Easton et al, 2003). The carbene intermediates are likely to form covalent complexes with the heme iron of CYP2D6, yielding the characteristic type 3 spectrum (Ortiz de Montellano, 1995).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…P450-mediated oxidation of the methylene carbon in both compounds would lead to formation of unstable intermediates, which are then demethylenated to catechols (3,4-dihydroxymethamphetamine and ␣-methyldopamine) or dehydrated to carbenes. The former compounds may be oxidized further to orthoquinones, which can react with nucleophilic groups on macromolecules or conjugate with glutathione to form neurotoxins (Easton et al, 2003). The carbene intermediates are likely to form covalent complexes with the heme iron of CYP2D6, yielding the characteristic type 3 spectrum (Ortiz de Montellano, 1995).…”
Section: Discussionmentioning
confidence: 99%
“…Although administration of MDMA and its metabolite methylenedioxyamphetamine to rats produces serotonergic nerve terminal degeneration, these compounds are not neurotoxic when injected directly into the brain. This suggests a requirement for their peripheral metabolism to neurotoxic metabolites (Easton et al, 2003) which, presumably, are then actively transported into the brain. These metabolites are believed to be downstream products formed after the opening of the methylendioxyphenyl ring, a process which is mainly mediated by CYP2D6 as a high-affinity enzyme (Tucker et al, 1994;Kreth et al, 2000), with low-affinity contributions from CYP1A2, CYP2B6, and CYP3A4 (Kreth et al, 2000).…”
mentioning
confidence: 99%
“…These ortho-metabolites and thioether-metabolites have a high redox potential, and several studies support their role mediating cytotoxicity in vivo and in vitro in different organs such as liver, brain, kidney, and heart (Easton et al 2003;Carvalho et al 2002;Carvalho, Remiao, Milhazes, Borges, Fernandes, Monteiro Mdo, et al 2004;Jones et al 2005;Capela et al 2007). …”
Section: Phase II Metabolismmentioning
confidence: 98%
“…Cytotoxicity of these metabolites has been shown not only in neurons [113] but also in other tissues such as cadiomyocytes [114] , hepatocytes [115,116] or human renal proximal tubular cells [117] . Importantly, these cytotoxic effects are aggravated under hyperthermic conditions [118,119] and can be formed by human liver microsomes in a CYP2D6-dependent manner [111,120] .…”
Section: Involvement Of Mdma Metabolism In the Mechanisms Underlying mentioning
confidence: 99%