Chemical modification at subunit 1 of rat kidney Alpha class glutathione transferase with 2,3,5,6-tetrachloro-1,4-benzoquinone: Close structural connectivity between glutathione conjugation activity and non-substrate ligand binding

O'Sullivan, Siobhan M.; McCarthy, Ronan M.; Vargo, Melissa A.; Colman, Roberta F.; Sheehan, David

doi:10.1016/j.bcp.2006.03.002

Cited by 2 publications

(1 citation statement)

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“…The role of the GSH S -transferases (GST) in these reactions is unclear. Thus, although GST catalyzes the conjugation of some catecholamine derived ortho -quinones with GSH , GSTs are also irreversibly inhibited by quinones and their GSH conjugates − . In particular, human GSTs are inhibited by dopamine, α-methyldopa, and by their 5- S -glutathionyl conjugates .…”

Section: Introductionmentioning

confidence: 99%

Serotonergic Neurotoxic Thioether Metabolites of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): Synthesis, Isolation, and Characterization of Diastereoisomers

Pizarro

Torre

Joglar

et al. 2008

Chem. Res. Toxicol.

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3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a synthetic recreational drug of abuse that produces long-term toxicity associated with the degeneration of serotonergic nerve terminals. In various animal models direct administration of MDMA into the brain fails to reproduce the serotonergic neurotoxicity, implying a requirement for the systemic metabolism and bioactivation of MDMA. Catechol-thioether metabolites of MDMA, formed via oxidation of 3,4-dihydroxymetamphetamine and 3,4-dihydroxyamphetamine (HHMA and HHA) and subsequent conjugation with glutathione (GSH), are selective serotonergic neurotoxicants when administered directly into brain. Moreover, following systemic administration of MDMA, the thioether adducts are present in rat brain dialysate. MDMA contains a stereogenic center, and is consumed as a racemate. Interestingly, different pharmacological properties have been attributed to the two enantiomers, (S)-MDMA being the most active in the central nervous system and responsible for the entactogenic effects, and most likely also for the neurodegeneration. The present study focused on the synthesis and stereochemical analysis of the neurotoxic MDMA thioether metabolites, 5-(glutathion-S-yl)-HHMA, 5-(N-acetylcysteine-S-yl)-HHMA, 2,5-bis-(glutathion-S-yl)-HHMA and 2,5-bis-(N-acetylcysteine-S-yl)-HHMA. Both enzymatic and electrochemical syntheses were explored, and methodologies for analytical and semi-preparative diastereoisomeric separation of MDMA thioether conjugates by HPLC-CEAS and HPLC-UV respectively were developed. Synthesis, diastereoisomeric separation, and unequivocal identification of the thioether conjugates of MDMA provide the chemical tools necessary for appropriate toxicological and metabolic studies on MDMA metabolites contributing to its neurotoxicity.

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