5-(Glutathion-S-yl)-α-methyldopamine [5-(GSyl)-α-MeDA] is a putative metabolite of the serotonergic neurotoxicants 3,4-(±)-(methylenedioxy)amphetamine and 3,4-(±)-(methylenedioxy)methamphetamine. Glutathione (GSH) conjugates of several polyphenols are biologically (re)active. Therefore, as part of our studies on the role of 5-(GSyl)-α-MeDA in MDA-mediated neurotoxicity, we determined the regional brain metabolism of 5-(GSyl)-α-MeDA (720 nmol) following intracerebroventricular administration to male Sprague-Dawley rats. 5-(GSyl)-α-MeDA was rapidly cleared from all brain regions examined, and regional differences in the distribution of γ-glutamyl transpeptidase (γ-GT) correlated with the formation of 5-(cystein-S-yl)-α-methyldopamine (5-[CYS]-α-MeDA). We also observed the formation of 5-(N-acetyl-L-cystein-S-yl)-α-MeDA (5-[NAC]-α-MeDA) in all brain regions, indicating that the brain has the ability to synthesize mercapturic acids. Peak concentrations of 5-(NAC)-α-MeDA were found in the order: hypothalamus > midbrain/diencephalon/telencephalon > pons/medulla > hippocampus > cortex > striatum. In contrast to 5-(GSyl)-α-MeDA and 5-(CYS)-α-MeDA, 5-(NAC)-α-MeDA was eliminated relatively slowly from the brain. Differences were also found in cysteine conjugate N-acetyltransferase activity in microsomes prepared from the various brain regions, but little difference was observed in brain cytosolic N-acetyl-L-cysteine conjugate N-deacetylase activity. We propose that some of the acute effects of 3,4•(±)-(methylenedioxy)-amphetamine and 3,4-(±)-(methylenedioxy)methamphetamine may be a consequence of the initial high concentrations of 5-(CYS)-α-MeDA, followed by the accumulation and persistence of 5-(NAC)-α-MeDA, which contributes to the long-term neurotoxicity. Because the mercapturic acid pathway can regulate the reactivity of quinones, our data may provide a biochemical basis for the heterogeneity in response of the brain to certain neurotoxicants.
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