Inhibition of biopterin synthesis and DOPA production in PC-12 pheochromocytoma cells induced by 6-aminonicotinamide
Identifieur interne : 002834 ( Main/Exploration ); précédent : 002833; suivant : 002835Inhibition of biopterin synthesis and DOPA production in PC-12 pheochromocytoma cells induced by 6-aminonicotinamide
Auteurs : W. Jung [Allemagne] ; H. Herken [Allemagne]Source :
- Naunyn-Schmiedeberg's Archives of Pharmacology [ 0028-1298 ] ; 1989-04-01.
Abstract
Summary: Pheochromocytoma cells (clone PC-12) were treated with 6-aminonicotinamide. Tetrahydrobiopterin content and DOPA production of the cells were determined by reverse-phase HPLC and subsequent electrochemical detection. The same chromatographic system was used to determine total biopterin (tetrahydrobiopterin, dihydrobiopterin and quinoide dihydrobiopterin) by fluorescence detection. Tetrahydrobiopterin plays a decisive role as cofactor of tyrosine hydroxylase for the biosynthesis of DOPA and dopamine. Addition of 6-aminonicotinamide to the culture medium resulted in the accumulation of 6-phosphogluconate, suggesting that PC-12 cells synthesize 6-aminonicotinamideadenine-dinucleotide-phosphate (6-ANADP) by a glycohydrolase localized in the endoplasmic reticulum. This substance is known to be a strong inhibitor of 6-phosphogluconate dehydrogenase and leads to a blockade of the pentose phosphate pathway. In our experiments, the synthesis of biopterins was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin by 6-aminonicotinamide at different concentrations was strongly correlated with a reduced cellular DOPA production. The decreased content of biopterin cofactor was compensated by addition of the precursor sepiapterin, indicating that the NADPH2-dependent reductases in biopterin synthesis are not inhibited by the antimetabolite. However, DOPA production rermained suppressed at the same time. After application of NADH2, we observed an increased DOPA production though the decreased biopterin levels remained almost unchanged. The results imply that the first step in the synthesis of biopterin from GTP as well as the recycling pathway of the oxidized cofactor might be the site of action of the antimetabolite. Restriction of the synthesis of the biopterin cofactor might be a pathogenetically important disorder at the initial phase of Parkinson's disease.
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DOI: 10.1007/BF00736057
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Herken</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:B8C4E8B3894A86DEEE14319D426F77A3AC626DEC</idno><date when="1989" year="1989">1989</date><idno type="doi">10.1007/BF00736057</idno><idno type="url">https://api.istex.fr/document/B8C4E8B3894A86DEEE14319D426F77A3AC626DEC/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001964</idno><idno type="wicri:Area/Main/Curation">001713</idno><idno type="wicri:Area/Main/Exploration">002834</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Inhibition of biopterin synthesis and DOPA production in PC-12 pheochromocytoma cells induced by 6-aminonicotinamide</title><author><name sortKey="Jung, W" sort="Jung, W" uniqKey="Jung W" first="W." last="Jung">W. Jung</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69/73, D-1000, Berlin 33</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Herken, H" sort="Herken, H" uniqKey="Herken H" first="H." last="Herken">H. Herken</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69/73, D-1000, Berlin 33</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Naunyn-Schmiedeberg's Archives of Pharmacology</title><title level="j" type="abbrev">Naunyn-Schmiedeberg's Arch. Pharmacol.</title><idno type="ISSN">0028-1298</idno><idno type="eISSN">1432-1912</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="1989-04-01">1989-04-01</date><biblScope unit="volume">339</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="424">424</biblScope><biblScope unit="page" to="432">432</biblScope></imprint><idno type="ISSN">0028-1298</idno></series><idno type="istex">B8C4E8B3894A86DEEE14319D426F77A3AC626DEC</idno><idno type="DOI">10.1007/BF00736057</idno><idno type="ArticleID">Art9</idno><idno type="ArticleID">BF00736057</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0028-1298</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Summary: Pheochromocytoma cells (clone PC-12) were treated with 6-aminonicotinamide. Tetrahydrobiopterin content and DOPA production of the cells were determined by reverse-phase HPLC and subsequent electrochemical detection. The same chromatographic system was used to determine total biopterin (tetrahydrobiopterin, dihydrobiopterin and quinoide dihydrobiopterin) by fluorescence detection. Tetrahydrobiopterin plays a decisive role as cofactor of tyrosine hydroxylase for the biosynthesis of DOPA and dopamine. Addition of 6-aminonicotinamide to the culture medium resulted in the accumulation of 6-phosphogluconate, suggesting that PC-12 cells synthesize 6-aminonicotinamideadenine-dinucleotide-phosphate (6-ANADP) by a glycohydrolase localized in the endoplasmic reticulum. This substance is known to be a strong inhibitor of 6-phosphogluconate dehydrogenase and leads to a blockade of the pentose phosphate pathway. In our experiments, the synthesis of biopterins was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin by 6-aminonicotinamide at different concentrations was strongly correlated with a reduced cellular DOPA production. The decreased content of biopterin cofactor was compensated by addition of the precursor sepiapterin, indicating that the NADPH2-dependent reductases in biopterin synthesis are not inhibited by the antimetabolite. However, DOPA production rermained suppressed at the same time. After application of NADH2, we observed an increased DOPA production though the decreased biopterin levels remained almost unchanged. The results imply that the first step in the synthesis of biopterin from GTP as well as the recycling pathway of the oxidized cofactor might be the site of action of the antimetabolite. Restriction of the synthesis of the biopterin cofactor might be a pathogenetically important disorder at the initial phase of Parkinson's disease.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Berlin</li></region><settlement><li>Berlin</li></settlement></list><tree><country name="Allemagne"><region name="Berlin"><name sortKey="Jung, W" sort="Jung, W" uniqKey="Jung W" first="W." last="Jung">W. Jung</name></region><name sortKey="Herken, H" sort="Herken, H" uniqKey="Herken H" first="H." last="Herken">H. Herken</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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