Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes
The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2...
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| Veröffentlicht in: | Journal of medicinal chemistry 1976-01, Vol.19 (1), p.174-177 |
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| container_title | Journal of medicinal chemistry |
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| creator | Sternson, Larry A Gammans, Richard E |
| description | The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes. |
| doi_str_mv | 10.1021/jm00223a034 |
| format | Article |
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Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00223a034</identifier><identifier>PMID: 1246040</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Aminopyrine - metabolism ; Aminopyrine - pharmacology ; Aniline Compounds - metabolism ; Aniline Compounds - pharmacology ; Aniline Hydroxylase - metabolism ; Animals ; Cytochrome P-450 Enzyme System - metabolism ; Energy Metabolism - drug effects ; Hexobarbital - metabolism ; Hexobarbital - pharmacology ; In Vitro Techniques ; Kinetics ; Male ; Microsomes, Liver - enzymology ; Microsomes, Liver - metabolism ; Mixed Function Oxygenases - metabolism ; Nitro Compounds - metabolism ; Nitro Compounds - pharmacology ; Oxidation-Reduction ; Rabbits ; Zoxazolamine - metabolism ; Zoxazolamine - pharmacology</subject><ispartof>Journal of medicinal chemistry, 1976-01, Vol.19 (1), p.174-177</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a354t-9c453ad26d6c9568ffcb4dd2f3f9c582c6787ebddfc16f13a0aee584c480fd2a3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00223a034$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00223a034$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1246040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sternson, Larry A</creatorcontrib><creatorcontrib>Gammans, Richard E</creatorcontrib><title>Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.</description><subject>Aminopyrine - metabolism</subject><subject>Aminopyrine - pharmacology</subject><subject>Aniline Compounds - metabolism</subject><subject>Aniline Compounds - pharmacology</subject><subject>Aniline Hydroxylase - metabolism</subject><subject>Animals</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Energy Metabolism - drug effects</subject><subject>Hexobarbital - metabolism</subject><subject>Hexobarbital - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Male</subject><subject>Microsomes, Liver - enzymology</subject><subject>Microsomes, Liver - metabolism</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Nitro Compounds - metabolism</subject><subject>Nitro Compounds - pharmacology</subject><subject>Oxidation-Reduction</subject><subject>Rabbits</subject><subject>Zoxazolamine - metabolism</subject><subject>Zoxazolamine - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1976</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1P3DAQxa0KBAv01HMln-CAAv5MssdqRQsCCSSWs3HssZplHW9tB7H89RgFlR56Gmneb97oPYS-UXJGCaPnK08IY1wTLr6gGZWMVKIlYgfN3vcVqxnfRwcprQghnDK-h_YoEzURZIYeL5wDk3FwWMfgde4NHvocAzbBb8I42ITDgMNLb4v2DNhD1l1Y98njbovNNgfzuxwCvquEJNjCBgYLQ8YwvG49pCO06_Q6wdePeYgefl4sF5fVze2vq8WPm0pzKXI1N0JybVltazOXdeuc6YS1zHE3N7Jlpm7aBjprnaG1oyWsBpCtMCWps0zzQ3Q8-W5i-DNCysr3ycB6rQcIY1ItZ5I1oing6QSaGFKK4NQm9l7HraJEvfep_umz0N8_bMfOg_1kpwKLXk16nzK8_JV1fFJ1wxuplnf3ql20y-vl_FJdF_5k4rVJahXGOJRS_vv5DUlXjQo</recordid><startdate>19760101</startdate><enddate>19760101</enddate><creator>Sternson, Larry A</creator><creator>Gammans, Richard E</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19760101</creationdate><title>Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes</title><author>Sternson, Larry A ; Gammans, Richard E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a354t-9c453ad26d6c9568ffcb4dd2f3f9c582c6787ebddfc16f13a0aee584c480fd2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1976</creationdate><topic>Aminopyrine - metabolism</topic><topic>Aminopyrine - pharmacology</topic><topic>Aniline Compounds - metabolism</topic><topic>Aniline Compounds - pharmacology</topic><topic>Aniline Hydroxylase - metabolism</topic><topic>Animals</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Energy Metabolism - drug effects</topic><topic>Hexobarbital - metabolism</topic><topic>Hexobarbital - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Male</topic><topic>Microsomes, Liver - enzymology</topic><topic>Microsomes, Liver - metabolism</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Nitro Compounds - metabolism</topic><topic>Nitro Compounds - pharmacology</topic><topic>Oxidation-Reduction</topic><topic>Rabbits</topic><topic>Zoxazolamine - metabolism</topic><topic>Zoxazolamine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sternson, Larry A</creatorcontrib><creatorcontrib>Gammans, Richard E</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sternson, Larry A</au><au>Gammans, Richard E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1976-01-01</date><risdate>1976</risdate><volume>19</volume><issue>1</issue><spage>174</spage><epage>177</epage><pages>174-177</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The effect of aromatic nitro compounds on the oxidative metabolism of representative type I (hexobarbital and aminopyrene) and type II (aniline and zoxazolamine) substrates by cytochrome P-450 dependent liver enzymes was studied. Nitro compounds (nitrobenzene, p-nitrobenzoate, 2-nitrofluorene, and 2-nitronaphthalene) inhibited the oxidation of type II substrates by rabbit liver microsomal enzymes; however, they had no effect on the metabolism of the type I compounds. Inhibition of type II metabolism was characterized graphically as S,I-hyperbolic non-competitive. The influence of aromatic nitro compounds on the interaction of type I and type II substrates with oxidized and reduced cytochrome P-450 was studied by difference spectroscopy. From Lineweaver-Burke plots, nitro compounds were shown to competitively interact with type II compounds for cytochrome p-450 binding sites. Nitro compounds completely prevented the appearance of a type I binding spectrum with either hexobarbital or aminopyrene even when the modifier was present at concentrations less than 10(-8)M. Aromatic nitro compounds appear to therefore inhibit the metabolism of the type II substrates through a mixed mechanism of interaction with the microsomal drug-metabolizing enzymes.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>1246040</pmid><doi>10.1021/jm00223a034</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1976-01, Vol.19 (1), p.174-177 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Aminopyrine - metabolism Aminopyrine - pharmacology Aniline Compounds - metabolism Aniline Compounds - pharmacology Aniline Hydroxylase - metabolism Animals Cytochrome P-450 Enzyme System - metabolism Energy Metabolism - drug effects Hexobarbital - metabolism Hexobarbital - pharmacology In Vitro Techniques Kinetics Male Microsomes, Liver - enzymology Microsomes, Liver - metabolism Mixed Function Oxygenases - metabolism Nitro Compounds - metabolism Nitro Compounds - pharmacology Oxidation-Reduction Rabbits Zoxazolamine - metabolism Zoxazolamine - pharmacology |
| title | Effect of aromatic nitro compounds on oxidative metabolism by cytochrome P-450 dependent enzymes |
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