Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations
Liver microsomes from uninduced mice and rats catalyze NADPH- and oxygen-dependent N-oxygenation of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of MPTP is d...
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| Veröffentlicht in: | Molecular pharmacology 1986-02, Vol.29 (2), p.163-167 |
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| creator | CASHMAN, J. R ZIEGLER, D. M |
| description | Liver microsomes from uninduced mice and rats catalyze NADPH- and oxygen-dependent N-oxygenation of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of
MPTP is detectable but the rate of nor-MPTP formation was never more than 4-6% of the rate of N-oxygenation. Studies on the
biochemical mechanisms for N-oxygenation of MPTP suggest that this reaction is catalyzed exclusively by the flavin-containing
monooxygenase. This conclusion is based on the effects of selective cytochrome P-450 inhibitors, positive effectors, and alternate
substrates for the flavin-containing monooxygenase as well as on studies with the purified hog liver enzyme. MPTP is an excellent
substrate for this monooxygenase with a Km of 30-33 microM. Limited studies with human liver whole homogenates suggest that
N-oxygenation is also a major route for the metabolism of MPTP in man and the rate of N-oxide formation is approximately equal
to the rate of mitochondrial monoamine oxidase-dependent MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species) production. |
| format | Article |
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The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of
MPTP is detectable but the rate of nor-MPTP formation was never more than 4-6% of the rate of N-oxygenation. Studies on the
biochemical mechanisms for N-oxygenation of MPTP suggest that this reaction is catalyzed exclusively by the flavin-containing
monooxygenase. This conclusion is based on the effects of selective cytochrome P-450 inhibitors, positive effectors, and alternate
substrates for the flavin-containing monooxygenase as well as on studies with the purified hog liver enzyme. MPTP is an excellent
substrate for this monooxygenase with a Km of 30-33 microM. Limited studies with human liver whole homogenates suggest that
N-oxygenation is also a major route for the metabolism of MPTP in man and the rate of N-oxide formation is approximately equal
to the rate of mitochondrial monoamine oxidase-dependent MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species) production.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 3485239</identifier><identifier>CODEN: MOPMA3</identifier><language>eng</language><publisher>Bethesda, MD: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Amines - pharmacology ; Animals ; Biological and medical sciences ; Drug addictions ; Female ; Flavins - physiology ; Humans ; In Vitro Techniques ; Inactivation, Metabolic ; Kinetics ; Liver - metabolism ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Microsomes, Liver - metabolism ; Oxidation-Reduction ; Oxygenases - physiology ; Pyridines - metabolism ; Rats ; Rats, Inbred Strains ; Toxicology</subject><ispartof>Molecular pharmacology, 1986-02, Vol.29 (2), p.163-167</ispartof><rights>1986 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=8711620$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3485239$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CASHMAN, J. R</creatorcontrib><creatorcontrib>ZIEGLER, D. M</creatorcontrib><title>Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>Liver microsomes from uninduced mice and rats catalyze NADPH- and oxygen-dependent N-oxygenation of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of
MPTP is detectable but the rate of nor-MPTP formation was never more than 4-6% of the rate of N-oxygenation. Studies on the
biochemical mechanisms for N-oxygenation of MPTP suggest that this reaction is catalyzed exclusively by the flavin-containing
monooxygenase. This conclusion is based on the effects of selective cytochrome P-450 inhibitors, positive effectors, and alternate
substrates for the flavin-containing monooxygenase as well as on studies with the purified hog liver enzyme. MPTP is an excellent
substrate for this monooxygenase with a Km of 30-33 microM. Limited studies with human liver whole homogenates suggest that
N-oxygenation is also a major route for the metabolism of MPTP in man and the rate of N-oxide formation is approximately equal
to the rate of mitochondrial monoamine oxidase-dependent MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species) production.</description><subject>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</subject><subject>Amines - pharmacology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Drug addictions</subject><subject>Female</subject><subject>Flavins - physiology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Inactivation, Metabolic</subject><subject>Kinetics</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microsomes, Liver - metabolism</subject><subject>Oxidation-Reduction</subject><subject>Oxygenases - physiology</subject><subject>Pyridines - metabolism</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Toxicology</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF9LwzAUxYMoc04_gpAHBYUFkqbtkkcZ_oOpe5jgW0nT2yXSNiXppn33g1u34dO5nPPjHjhHaMySiBHKGDtGY0qjlAiZfJyisxA-KWVxIugIjXgskojLMfqZu6bzNt901jXYlfiVuO9-DY3aGZ3DnQFcQ6dyV9lQ_yEvy9US3zAyuKavSExaA81wsGk05dOUdNB5ZfrCu7b3trAN3OK8x1vlrdsEXNkteNx6aJXftYRzdFKqKsDFQSfo_eF-NX8ii7fH5_ndgpgoTToieJwAS1NR5kIoGjMlc5rIUqYSRCxmIk-oZoUWBeWyhAKo5jNacuBaSwrAJ-hy_7fd5DUUWettrXyfHdYY8qtDroJWVelVo234x8SMsTSiA3a9x4xdmy_rIWuN8rXSrnLrPotkFmUs5fwX6cJ3UQ</recordid><startdate>19860201</startdate><enddate>19860201</enddate><creator>CASHMAN, J. R</creator><creator>ZIEGLER, D. M</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19860201</creationdate><title>Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations</title><author>CASHMAN, J. R ; ZIEGLER, D. M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h265t-8345e1668fb88a041a9b059f969e84878b50c1dc8d039fede0c370f3e3cc90ee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1986</creationdate><topic>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</topic><topic>Amines - pharmacology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Drug addictions</topic><topic>Female</topic><topic>Flavins - physiology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Inactivation, Metabolic</topic><topic>Kinetics</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microsomes, Liver - metabolism</topic><topic>Oxidation-Reduction</topic><topic>Oxygenases - physiology</topic><topic>Pyridines - metabolism</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CASHMAN, J. R</creatorcontrib><creatorcontrib>ZIEGLER, D. M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CASHMAN, J. R</au><au>ZIEGLER, D. M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>1986-02-01</date><risdate>1986</risdate><volume>29</volume><issue>2</issue><spage>163</spage><epage>167</epage><pages>163-167</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><coden>MOPMA3</coden><abstract>Liver microsomes from uninduced mice and rats catalyze NADPH- and oxygen-dependent N-oxygenation of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of
MPTP is detectable but the rate of nor-MPTP formation was never more than 4-6% of the rate of N-oxygenation. Studies on the
biochemical mechanisms for N-oxygenation of MPTP suggest that this reaction is catalyzed exclusively by the flavin-containing
monooxygenase. This conclusion is based on the effects of selective cytochrome P-450 inhibitors, positive effectors, and alternate
substrates for the flavin-containing monooxygenase as well as on studies with the purified hog liver enzyme. MPTP is an excellent
substrate for this monooxygenase with a Km of 30-33 microM. Limited studies with human liver whole homogenates suggest that
N-oxygenation is also a major route for the metabolism of MPTP in man and the rate of N-oxide formation is approximately equal
to the rate of mitochondrial monoamine oxidase-dependent MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species) production.</abstract><cop>Bethesda, MD</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>3485239</pmid><tpages>5</tpages></addata></record> |
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| ispartof | Molecular pharmacology, 1986-02, Vol.29 (2), p.163-167 |
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| language | eng |
| recordid | cdi_pubmed_primary_3485239 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Amines - pharmacology Animals Biological and medical sciences Drug addictions Female Flavins - physiology Humans In Vitro Techniques Inactivation, Metabolic Kinetics Liver - metabolism Male Medical sciences Mice Mice, Inbred C57BL Microsomes, Liver - metabolism Oxidation-Reduction Oxygenases - physiology Pyridines - metabolism Rats Rats, Inbred Strains Toxicology |
| title | Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations |
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