Patients with glutaryl-CoA dehydrogenase (GCDH) deficiency accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3OH-GA) in their blood and urine. To identify the transporter mediating the translocation of 3OH-GA through membranes, kidney tissue of Gcdh-/- mice have been investigated because of its central role in urinary excretion of this metabolite. Using microarray analyses of kidney-expressed genes in Gcdh-/- mice, several differentially expressed genes encoding transporter proteins were identified. Real-time polymerase chain reaction analysis confirmed the upregulation of the sodium-dependent dicarboxylate cotransporter 3 (NaDC3) and the organic cation transporter 2 (OCT2). Expression analysis of NaDC3 in Xenopus laevis oocytes by the two-electrode-voltage-clamp technique demonstrated the sodium-dependent translocation of 3OH-GA with a K (M) value of 0.95 mM. Furthermore, tracer flux measurements in Chinese hamster ovary cells overexpressing OCT2 showed that 3OH-GA inhibited significantly the uptake of methyl-4-phenylpyridinium, whereas 3OH-GA is not transported by OCT2. The data demonstrate for the first time the membrane translocation of 3OH-GA mediated by NaDC3 and the cis-inhibitory effect on OCT2-mediated transport of cations.
Glutaric aciduria type 1 (GA1) is caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH). Affected patients are prone to the development of encephalopathic crises during an early time window with destruction of striatal neurons and a subsequent irreversible movement disorder. 3-Hydroxyglutaric acid (3OHGA) accumulates in tissues and body fluids of GA1 patients and has been shown to mediate toxic effects on neuronal as well as endothelial cells. Injection of (3H)-labeled into 6 week-old Gcdh(-/-) mice, a model of GA1, revealed a low recovery in kidney, liver, or brain tissue that did not differ from control mice. Significant amounts of 3OHGA were found to be excreted via the intestinal tract. Exposure of Gcdh(-/-) mice to a high protein diet led to an encephalopathic crisis, vacuolization in the brain, and death after 4-5 days. Under these conditions, high amounts of injected 3H-3OHGA were found in kidneys of Gcdh(-/-) mice, whereas the radioactivity recovered in brain and blood was reduced. The data demonstrate that under conditions mimicking encephalopathic crises the blood-brain barrier appears to remain intact.
Summary
N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-[18 F]fluoroheptylammonium ([ 18 F]-fluoroclofilium) has been prepared as a potential cardiac imaging agent. For the synthesis of this radiolabelled ammonium salt, its tosyloxylated analogue was prepared as a precursor, and the non-radioactive fluorine analogue was synthesized as a reference compound. Radiofluorination was achieved by the treatment of N-4-(4-chlorophenyl)butyl-N,N-diethyl-7-(p-toluenesulfonyloxy)-heptylammonium p-toluenesulfonate with 18 F À in the presence of Kryptofix-2.2.2 in acetonitrile.
Bei der Umlagerung von N-Sulfonyloxy-Derivaten des 2-Azabicyclo[2.2. llheptans und -hept-5-ens (z. B. 9, 11) in bicyclische Systeme mit Stickstoff als Briickenkopfatom (10, 12) sprechen folgende Befunde fur einen ionischen Ablauf, der weitgehend uber enge Ionenpaare erfolgt: 1. Bei Versuchen mit "0-indizierten Substanzen tritt partielles '80-Aquilibrieren ein, das von der Struktur der Edukte und vom Losungsmittel beeinfluat wird. 2. In Methanol konnen die intermediaren Carbenium-Ionen (19, 23) als Methoxyverbindungen abgefangen werden. 3. MIND0/3-Rechnungen ') stimmen damit uberein: a) Im gesattigten System ist das Nitrenium-Ion 20 stabil. b) Die optimierten Geometrien der umgelagerten Carbenium-Ionen (21, 23) entsprechen in beiden Systemen den durch die Abfangversuche ermittelten Strukturen.
Nitrenium and Carbenium Ions in Rearrangements of 2-Azabicyclic SystemsAn ionic mechanism proceeding in intimate ion pairs is suggested for the rearrangement of N-sulfonyloxy derivatives of 2-azabicyclo[2.2.l]heptane and -hept-5-ene (e. g. 9, 11 + 10, 12). 1 . Experiments with labelled educts show partial scrambling dependend both on structure of educt and solvent.
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