Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450
In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirm...
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| Veröffentlicht in: | Biochemistry (Easton) 1989-06, Vol.28 (12), p.5128-5136 |
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| creator | DECKER, C. J RASHED, M. S BAILLIE, T. A MALTBY, D CORREIA, M. A |
| description | In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, we have examined the metabolism of SPL in vitro. Incubation of [14C]SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O2, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass spectral analysis (thermospray LC/MS, FAB/MS, and FAB/MS/MS) of the two most prominent polar metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These findings document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p. |
| doi_str_mv | 10.1021/bi00438a033 |
| format | Article |
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J ; RASHED, M. S ; BAILLIE, T. A ; MALTBY, D ; CORREIA, M. A</creator><creatorcontrib>DECKER, C. J ; RASHED, M. S ; BAILLIE, T. A ; MALTBY, D ; CORREIA, M. A</creatorcontrib><description>In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, we have examined the metabolism of SPL in vitro. Incubation of [14C]SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O2, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass spectral analysis (thermospray LC/MS, FAB/MS, and FAB/MS/MS) of the two most prominent polar metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These findings document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi00438a033</identifier><identifier>PMID: 2765527</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>550201 - Biochemistry- Tracer Techniques ; ADRENAL HORMONES ; ANIMALS ; BASIC BIOLOGICAL SCIENCES ; Binding Sites ; Biological and medical sciences ; BODY ; CARBON 14 COMPOUNDS ; CELL CONSTITUENTS ; Cell metabolism, cell oxidation ; Cell physiology ; CHEMICAL REACTIONS ; Chromatography, High Pressure Liquid ; CORTICOSTEROIDS ; Cytochrome P-450 Enzyme Inhibitors ; cytochrome p450 ; CYTOCHROMES ; Dexamethasone - pharmacology ; DIGESTIVE SYSTEM ; Enzyme Induction - drug effects ; ESTERS ; Fundamental and applied biological sciences. Psychology ; GLANDS ; HETEROCYCLIC COMPOUNDS ; HYDROXY COMPOUNDS ; INACTIVATION ; ISOENZYMES ; Isoenzymes - antagonists & inhibitors ; KETONES ; Kinetics ; LABELLED COMPOUNDS ; LACTONES ; LIVER ; Male ; MAMMALS ; Mass Spectrometry ; METABOLISM ; METABOLITES ; MICROSOMES ; Microsomes, Liver - drug effects ; Microsomes, Liver - enzymology ; Molecular and cellular biology ; Molecular Structure ; NADP - pharmacology ; ORGANIC COMPOUNDS ; ORGANIC SULFUR COMPOUNDS ; ORGANOIDS ; ORGANS ; OXIDATION ; Oxidation-Reduction ; PIGMENTS ; PREGNANES ; PROTEINS ; RATS ; Rats, Inbred Strains ; RIBOSOMES ; RODENTS ; Spectrophotometry, Ultraviolet ; Spironolactone - analysis ; Spironolactone - metabolism ; STEROIDS ; Sulfinic Acids - analysis ; Sulfonic Acids - analysis ; THIOLS ; VERTEBRATES</subject><ispartof>Biochemistry (Easton), 1989-06, Vol.28 (12), p.5128-5136</ispartof><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19284798$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2765527$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/5443427$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>DECKER, C. J</creatorcontrib><creatorcontrib>RASHED, M. S</creatorcontrib><creatorcontrib>BAILLIE, T. A</creatorcontrib><creatorcontrib>MALTBY, D</creatorcontrib><creatorcontrib>CORREIA, M. A</creatorcontrib><title>Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, we have examined the metabolism of SPL in vitro. Incubation of [14C]SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O2, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass spectral analysis (thermospray LC/MS, FAB/MS, and FAB/MS/MS) of the two most prominent polar metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These findings document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p.</description><subject>550201 - Biochemistry- Tracer Techniques</subject><subject>ADRENAL HORMONES</subject><subject>ANIMALS</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>BODY</subject><subject>CARBON 14 COMPOUNDS</subject><subject>CELL CONSTITUENTS</subject><subject>Cell metabolism, cell oxidation</subject><subject>Cell physiology</subject><subject>CHEMICAL REACTIONS</subject><subject>Chromatography, High Pressure Liquid</subject><subject>CORTICOSTEROIDS</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>cytochrome p450</subject><subject>CYTOCHROMES</subject><subject>Dexamethasone - pharmacology</subject><subject>DIGESTIVE SYSTEM</subject><subject>Enzyme Induction - drug effects</subject><subject>ESTERS</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GLANDS</subject><subject>HETEROCYCLIC COMPOUNDS</subject><subject>HYDROXY COMPOUNDS</subject><subject>INACTIVATION</subject><subject>ISOENZYMES</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>KETONES</subject><subject>Kinetics</subject><subject>LABELLED COMPOUNDS</subject><subject>LACTONES</subject><subject>LIVER</subject><subject>Male</subject><subject>MAMMALS</subject><subject>Mass Spectrometry</subject><subject>METABOLISM</subject><subject>METABOLITES</subject><subject>MICROSOMES</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - enzymology</subject><subject>Molecular and cellular biology</subject><subject>Molecular Structure</subject><subject>NADP - pharmacology</subject><subject>ORGANIC COMPOUNDS</subject><subject>ORGANIC SULFUR COMPOUNDS</subject><subject>ORGANOIDS</subject><subject>ORGANS</subject><subject>OXIDATION</subject><subject>Oxidation-Reduction</subject><subject>PIGMENTS</subject><subject>PREGNANES</subject><subject>PROTEINS</subject><subject>RATS</subject><subject>Rats, Inbred Strains</subject><subject>RIBOSOMES</subject><subject>RODENTS</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Spironolactone - analysis</subject><subject>Spironolactone - metabolism</subject><subject>STEROIDS</subject><subject>Sulfinic Acids - analysis</subject><subject>Sulfonic Acids - analysis</subject><subject>THIOLS</subject><subject>VERTEBRATES</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2LFDEQhoMo67h68iwEQW-tla9JtzdZ_IKF9bD3JpNU2yXdSZtkBvcH-T_NsoNXT0VRT728bxVjLwW8EyDF-wMBaNU7UOoR2wkjodPDYB6zHQDsOzns4Sl7VsrP1mqw-oJdSLs3Rtod-3Pzm4KrdEK-YnWHtFBZeZp42SinmBbna4r4geOJAkaPfEqZ1xk5xVNaTrhirPc8LuhrTttMC_kGUCoVc6LQlNATlrbAQz7-6FYM5CoGHrDUfPSVUrxXyK7yGbdmxnN_V5Ofc1qRf9cGnrMnk1sKvjjXS3b7-dPt1dfu-ubLt6uP112Sg67dJHqlhAMtrJG9Ueid90o6Cc6iDi4IqRUEZUEIDYdBONcDSD-145m2e8leP8g27zQWTxX97FOMLdpotFZa2ga9fYC2nH4dW4RxpeJxWVzEdCyjHYTp-0H_FxRGK2EsNPDVGTwe2nHGLdPq8t14flKbvznPXfFumbKLnso_TAyy13bo1V8jn6Kb</recordid><startdate>19890613</startdate><enddate>19890613</enddate><creator>DECKER, C. 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A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-o294t-f18331a041752853ecacc32a20a7e4dad12430d3701140b91aa8002cf38a5183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>550201 - Biochemistry- Tracer Techniques</topic><topic>ADRENAL HORMONES</topic><topic>ANIMALS</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>BODY</topic><topic>CARBON 14 COMPOUNDS</topic><topic>CELL CONSTITUENTS</topic><topic>Cell metabolism, cell oxidation</topic><topic>Cell physiology</topic><topic>CHEMICAL REACTIONS</topic><topic>Chromatography, High Pressure Liquid</topic><topic>CORTICOSTEROIDS</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>cytochrome p450</topic><topic>CYTOCHROMES</topic><topic>Dexamethasone - pharmacology</topic><topic>DIGESTIVE SYSTEM</topic><topic>Enzyme Induction - drug effects</topic><topic>ESTERS</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>GLANDS</topic><topic>HETEROCYCLIC COMPOUNDS</topic><topic>HYDROXY COMPOUNDS</topic><topic>INACTIVATION</topic><topic>ISOENZYMES</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>KETONES</topic><topic>Kinetics</topic><topic>LABELLED COMPOUNDS</topic><topic>LACTONES</topic><topic>LIVER</topic><topic>Male</topic><topic>MAMMALS</topic><topic>Mass Spectrometry</topic><topic>METABOLISM</topic><topic>METABOLITES</topic><topic>MICROSOMES</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - enzymology</topic><topic>Molecular and cellular biology</topic><topic>Molecular Structure</topic><topic>NADP - pharmacology</topic><topic>ORGANIC COMPOUNDS</topic><topic>ORGANIC SULFUR COMPOUNDS</topic><topic>ORGANOIDS</topic><topic>ORGANS</topic><topic>OXIDATION</topic><topic>Oxidation-Reduction</topic><topic>PIGMENTS</topic><topic>PREGNANES</topic><topic>PROTEINS</topic><topic>RATS</topic><topic>Rats, Inbred Strains</topic><topic>RIBOSOMES</topic><topic>RODENTS</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Spironolactone - analysis</topic><topic>Spironolactone - metabolism</topic><topic>STEROIDS</topic><topic>Sulfinic Acids - analysis</topic><topic>Sulfonic Acids - analysis</topic><topic>THIOLS</topic><topic>VERTEBRATES</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DECKER, C. 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A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>1989-06-13</date><risdate>1989</risdate><volume>28</volume><issue>12</issue><spage>5128</spage><epage>5136</epage><pages>5128-5136</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, we have examined the metabolism of SPL in vitro. Incubation of [14C]SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O2, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass spectral analysis (thermospray LC/MS, FAB/MS, and FAB/MS/MS) of the two most prominent polar metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These findings document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2765527</pmid><doi>10.1021/bi00438a033</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Biochemistry (Easton), 1989-06, Vol.28 (12), p.5128-5136 |
| issn | 0006-2960 1520-4995 |
| language | eng |
| recordid | cdi_osti_scitechconnect_5443427 |
| source | ACS Publications; MEDLINE |
| subjects | 550201 - Biochemistry- Tracer Techniques ADRENAL HORMONES ANIMALS BASIC BIOLOGICAL SCIENCES Binding Sites Biological and medical sciences BODY CARBON 14 COMPOUNDS CELL CONSTITUENTS Cell metabolism, cell oxidation Cell physiology CHEMICAL REACTIONS Chromatography, High Pressure Liquid CORTICOSTEROIDS Cytochrome P-450 Enzyme Inhibitors cytochrome p450 CYTOCHROMES Dexamethasone - pharmacology DIGESTIVE SYSTEM Enzyme Induction - drug effects ESTERS Fundamental and applied biological sciences. Psychology GLANDS HETEROCYCLIC COMPOUNDS HYDROXY COMPOUNDS INACTIVATION ISOENZYMES Isoenzymes - antagonists & inhibitors KETONES Kinetics LABELLED COMPOUNDS LACTONES LIVER Male MAMMALS Mass Spectrometry METABOLISM METABOLITES MICROSOMES Microsomes, Liver - drug effects Microsomes, Liver - enzymology Molecular and cellular biology Molecular Structure NADP - pharmacology ORGANIC COMPOUNDS ORGANIC SULFUR COMPOUNDS ORGANOIDS ORGANS OXIDATION Oxidation-Reduction PIGMENTS PREGNANES PROTEINS RATS Rats, Inbred Strains RIBOSOMES RODENTS Spectrophotometry, Ultraviolet Spironolactone - analysis Spironolactone - metabolism STEROIDS Sulfinic Acids - analysis Sulfonic Acids - analysis THIOLS VERTEBRATES |
| title | Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450 |
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