Linked Life Data

11453733

Source:http://linkedlifedata.com/resource/pubmed/id/11453733

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2001-7-16
pubmed:abstractText
Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT) suggesting competition between intact 5-GSyl-alpha-MeDA and GSH for the putative GSH transporter. gamma-GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma-GT at the blood-brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis-(glutathion-S-yl)-alpha-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
14
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
863-70
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11453733-3,4-Methylenedioxyamphetamine, pubmed-meshheading:11453733-Administration, Cutaneous, pubmed-meshheading:11453733-Animals, pubmed-meshheading:11453733-Brain, pubmed-meshheading:11453733-Endothelium, pubmed-meshheading:11453733-Enzyme Inhibitors, pubmed-meshheading:11453733-Humans, pubmed-meshheading:11453733-Isoxazoles, pubmed-meshheading:11453733-Male, pubmed-meshheading:11453733-Models, Molecular, pubmed-meshheading:11453733-N-Methyl-3,4-methylenedioxyamphetamine, pubmed-meshheading:11453733-Neurotoxicity Syndromes, pubmed-meshheading:11453733-Neurotransmitter Agents, pubmed-meshheading:11453733-Rats, pubmed-meshheading:11453733-Rats, Sprague-Dawley, pubmed-meshheading:11453733-Serotonin, pubmed-meshheading:11453733-Serotonin Agents, pubmed-meshheading:11453733-gamma-Glutamyltransferase
pubmed:year
2001
pubmed:articleTitle
Serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase.
pubmed:affiliation
Center for Cellular and Molecular Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712-1074, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.