The metabolism of pentachlorobenzene by rat liver microsomes: The nature of the reactive intermediates formed
Metabolism of [ 14C]-pentachlorobenzene by liver microsomes from dexamethasone-induced rats results in the formation of pentachlorophenol and 2,3,4,6-tetrachlorphenol as major primary metabolites in a ratio of 4:1, with 2,3,4,5- and 2,3,5,6-tetrachlorophenols as minor metabolites. The unsubstituted...
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| Veröffentlicht in: | Biochemical and biophysical research communications 1989-09, Vol.163 (3), p.1275-1281 |
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| creator | den Besten, C. Peters, M.M.C.G. van Bladeren, P.J. |
| description | Metabolism of [
14C]-pentachlorobenzene by liver microsomes from dexamethasone-induced rats results in the formation of pentachlorophenol and 2,3,4,6-tetrachlorphenol as major primary metabolites in a ratio of 4:1, with 2,3,4,5- and 2,3,5,6-tetrachlorophenols as minor metabolites. The unsubstituted carbon atom is thus the favourite site of oxidative attack, but the chlorine substituted positions still play a sizable role. As secondary metabolites both para- and ortho-tetrachlorohydroquinone are formed (1.4 and 0.9 % of total metabolites respectively). During this cytochrome P450-dependent conversion of pentachlorobenzene, 5–15 % of the total amount of metabolites becomes covalently bound to microsomal protein. Ascorbic acid inhibits this binding to a considerable extent, indicating that quinone metabolites play an important role in the binding. However, complete inhibition was never reached by ascorbic acid, nor by glutathione, suggesting that other reactive intermediates, presumably epoxides, are also responsible for covalent binding. |
| doi_str_mv | 10.1016/0006-291X(89)91116-9 |
| format | Article |
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14C]-pentachlorobenzene by liver microsomes from dexamethasone-induced rats results in the formation of pentachlorophenol and 2,3,4,6-tetrachlorphenol as major primary metabolites in a ratio of 4:1, with 2,3,4,5- and 2,3,5,6-tetrachlorophenols as minor metabolites. The unsubstituted carbon atom is thus the favourite site of oxidative attack, but the chlorine substituted positions still play a sizable role. As secondary metabolites both para- and ortho-tetrachlorohydroquinone are formed (1.4 and 0.9 % of total metabolites respectively). During this cytochrome P450-dependent conversion of pentachlorobenzene, 5–15 % of the total amount of metabolites becomes covalently bound to microsomal protein. Ascorbic acid inhibits this binding to a considerable extent, indicating that quinone metabolites play an important role in the binding. However, complete inhibition was never reached by ascorbic acid, nor by glutathione, suggesting that other reactive intermediates, presumably epoxides, are also responsible for covalent binding.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/0006-291X(89)91116-9</identifier><identifier>PMID: 2675838</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>550501 - Metabolism- Tracer Techniques ; 560300 - Chemicals Metabolism & Toxicology ; ADRENAL HORMONES ; ANIMALS ; AROMATICS ; ASCORBIC ACID ; BASIC BIOLOGICAL SCIENCES ; Biotransformation ; BODY ; CARBON 14 COMPOUNDS ; Carbon Radioisotopes ; CELL CONSTITUENTS ; CHLORINATED AROMATIC HYDROCARBONS ; Chlorobenzenes - metabolism ; CHROMATOGRAPHY ; Chromatography, High Pressure Liquid ; CORTICOSTEROIDS ; DEXAMETHASONE ; Dexamethasone - pharmacology ; DIGESTIVE SYSTEM ; DRUGS ; ENZYMES ; GLANDS ; GLUCOCORTICOIDS ; GLUTATHIONE ; HALOGENATED AROMATIC HYDROCARBONS ; HYDROXY COMPOUNDS ; Insecticides - metabolism ; ISOTOPE APPLICATIONS ; KETONES ; LABELLED COMPOUNDS ; LIQUID COLUMN CHROMATOGRAPHY ; LIVER ; Male ; MAMMALS ; METABOLISM ; METABOLITES ; MICROSOMES ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; MIXED-FUNCTION OXIDASES ; ORGANIC CHLORINE COMPOUNDS ; ORGANIC COMPOUNDS ; ORGANIC HALOGEN COMPOUNDS ; ORGANOIDS ; ORGANS ; OXIDOREDUCTASES ; OXYGENASES ; PEPTIDES ; POLYPEPTIDES ; PREGNANES ; PROTEINS ; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT ; Radioisotope Dilution Technique ; RADIOPROTECTIVE SUBSTANCES ; RATS ; Rats, Inbred Strains ; RIBOSOMES ; RODENTS ; SEPARATION PROCESSES ; STEROIDS ; TRACER TECHNIQUES ; VERTEBRATES ; VITAMINS</subject><ispartof>Biochemical and biophysical research communications, 1989-09, Vol.163 (3), p.1275-1281</ispartof><rights>1989</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-35bc4d01210eff6e21bf1ab3c12ce0035317d0478690d1f7eb098a89184559383</citedby><cites>FETCH-LOGICAL-c415t-35bc4d01210eff6e21bf1ab3c12ce0035317d0478690d1f7eb098a89184559383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0006-291X(89)91116-9$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3538,27906,27907,45977</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2675838$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/5465343$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>den Besten, C.</creatorcontrib><creatorcontrib>Peters, M.M.C.G.</creatorcontrib><creatorcontrib>van Bladeren, P.J.</creatorcontrib><title>The metabolism of pentachlorobenzene by rat liver microsomes: The nature of the reactive intermediates formed</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Metabolism of [
14C]-pentachlorobenzene by liver microsomes from dexamethasone-induced rats results in the formation of pentachlorophenol and 2,3,4,6-tetrachlorphenol as major primary metabolites in a ratio of 4:1, with 2,3,4,5- and 2,3,5,6-tetrachlorophenols as minor metabolites. The unsubstituted carbon atom is thus the favourite site of oxidative attack, but the chlorine substituted positions still play a sizable role. As secondary metabolites both para- and ortho-tetrachlorohydroquinone are formed (1.4 and 0.9 % of total metabolites respectively). During this cytochrome P450-dependent conversion of pentachlorobenzene, 5–15 % of the total amount of metabolites becomes covalently bound to microsomal protein. Ascorbic acid inhibits this binding to a considerable extent, indicating that quinone metabolites play an important role in the binding. However, complete inhibition was never reached by ascorbic acid, nor by glutathione, suggesting that other reactive intermediates, presumably epoxides, are also responsible for covalent binding.</description><subject>550501 - Metabolism- Tracer Techniques</subject><subject>560300 - Chemicals Metabolism & Toxicology</subject><subject>ADRENAL HORMONES</subject><subject>ANIMALS</subject><subject>AROMATICS</subject><subject>ASCORBIC ACID</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Biotransformation</subject><subject>BODY</subject><subject>CARBON 14 COMPOUNDS</subject><subject>Carbon Radioisotopes</subject><subject>CELL CONSTITUENTS</subject><subject>CHLORINATED AROMATIC HYDROCARBONS</subject><subject>Chlorobenzenes - metabolism</subject><subject>CHROMATOGRAPHY</subject><subject>Chromatography, High Pressure Liquid</subject><subject>CORTICOSTEROIDS</subject><subject>DEXAMETHASONE</subject><subject>Dexamethasone - pharmacology</subject><subject>DIGESTIVE SYSTEM</subject><subject>DRUGS</subject><subject>ENZYMES</subject><subject>GLANDS</subject><subject>GLUCOCORTICOIDS</subject><subject>GLUTATHIONE</subject><subject>HALOGENATED AROMATIC HYDROCARBONS</subject><subject>HYDROXY COMPOUNDS</subject><subject>Insecticides - metabolism</subject><subject>ISOTOPE APPLICATIONS</subject><subject>KETONES</subject><subject>LABELLED COMPOUNDS</subject><subject>LIQUID COLUMN CHROMATOGRAPHY</subject><subject>LIVER</subject><subject>Male</subject><subject>MAMMALS</subject><subject>METABOLISM</subject><subject>METABOLITES</subject><subject>MICROSOMES</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>MIXED-FUNCTION OXIDASES</subject><subject>ORGANIC CHLORINE COMPOUNDS</subject><subject>ORGANIC COMPOUNDS</subject><subject>ORGANIC HALOGEN COMPOUNDS</subject><subject>ORGANOIDS</subject><subject>ORGANS</subject><subject>OXIDOREDUCTASES</subject><subject>OXYGENASES</subject><subject>PEPTIDES</subject><subject>POLYPEPTIDES</subject><subject>PREGNANES</subject><subject>PROTEINS</subject><subject>RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT</subject><subject>Radioisotope Dilution Technique</subject><subject>RADIOPROTECTIVE SUBSTANCES</subject><subject>RATS</subject><subject>Rats, Inbred Strains</subject><subject>RIBOSOMES</subject><subject>RODENTS</subject><subject>SEPARATION PROCESSES</subject><subject>STEROIDS</subject><subject>TRACER TECHNIQUES</subject><subject>VERTEBRATES</subject><subject>VITAMINS</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU-LFDEQxYMo67j6DRSCB9FDa6qTTiceBFn8BwteVvAW0ulqJtKdjElmYf30Js6wR09JqN-r1HtFyHNgb4GBfMcYk12v4edrpd9oAJCdfkB2wDTremDiIdndI4_Jk5x_MQYgpL4gF70cB8XVjmw3e6QbFjvF1eeNxoUeMBTr9mtMccLwBwPS6Y4mW-jqbzHRzbsUc9wwv6dNHWw5JmzKUl8JrSuVoz4UTBvO3hbMdInt_pQ8Wuya8dn5vCQ_Pn-6ufraXX__8u3q43XnBAyl48PkxMygusBlkdjDtICduIPeIWN84DDOTIxKajbDMuLEtLJKgxLDoLnil-TlqW_MxZvsfEG3dzEEdMUMQg5c8Aq9OkGHFH8fMRez-exwXW3AeMwGBgEjl7qC4gQ23znhYg7JbzbdGWCmrcK0nE3L2Sht_q3CNNmLc__jVL3fi87Z1_qHUx1rErceUxsUg6uRpTbnHP3_P_gLXMaYzA</recordid><startdate>19890929</startdate><enddate>19890929</enddate><creator>den Besten, C.</creator><creator>Peters, M.M.C.G.</creator><creator>van Bladeren, P.J.</creator><general>Elsevier Inc</general><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>7U7</scope><scope>C1K</scope><scope>OTOTI</scope></search><sort><creationdate>19890929</creationdate><title>The metabolism of pentachlorobenzene by rat liver microsomes: The nature of the reactive intermediates formed</title><author>den Besten, C. ; Peters, M.M.C.G. ; van Bladeren, P.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-35bc4d01210eff6e21bf1ab3c12ce0035317d0478690d1f7eb098a89184559383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>550501 - Metabolism- Tracer Techniques</topic><topic>560300 - Chemicals Metabolism & Toxicology</topic><topic>ADRENAL HORMONES</topic><topic>ANIMALS</topic><topic>AROMATICS</topic><topic>ASCORBIC ACID</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Biotransformation</topic><topic>BODY</topic><topic>CARBON 14 COMPOUNDS</topic><topic>Carbon Radioisotopes</topic><topic>CELL CONSTITUENTS</topic><topic>CHLORINATED AROMATIC HYDROCARBONS</topic><topic>Chlorobenzenes - metabolism</topic><topic>CHROMATOGRAPHY</topic><topic>Chromatography, High Pressure Liquid</topic><topic>CORTICOSTEROIDS</topic><topic>DEXAMETHASONE</topic><topic>Dexamethasone - pharmacology</topic><topic>DIGESTIVE SYSTEM</topic><topic>DRUGS</topic><topic>ENZYMES</topic><topic>GLANDS</topic><topic>GLUCOCORTICOIDS</topic><topic>GLUTATHIONE</topic><topic>HALOGENATED AROMATIC HYDROCARBONS</topic><topic>HYDROXY COMPOUNDS</topic><topic>Insecticides - metabolism</topic><topic>ISOTOPE APPLICATIONS</topic><topic>KETONES</topic><topic>LABELLED COMPOUNDS</topic><topic>LIQUID COLUMN CHROMATOGRAPHY</topic><topic>LIVER</topic><topic>Male</topic><topic>MAMMALS</topic><topic>METABOLISM</topic><topic>METABOLITES</topic><topic>MICROSOMES</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>MIXED-FUNCTION OXIDASES</topic><topic>ORGANIC CHLORINE COMPOUNDS</topic><topic>ORGANIC COMPOUNDS</topic><topic>ORGANIC HALOGEN COMPOUNDS</topic><topic>ORGANOIDS</topic><topic>ORGANS</topic><topic>OXIDOREDUCTASES</topic><topic>OXYGENASES</topic><topic>PEPTIDES</topic><topic>POLYPEPTIDES</topic><topic>PREGNANES</topic><topic>PROTEINS</topic><topic>RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT</topic><topic>Radioisotope Dilution Technique</topic><topic>RADIOPROTECTIVE SUBSTANCES</topic><topic>RATS</topic><topic>Rats, Inbred Strains</topic><topic>RIBOSOMES</topic><topic>RODENTS</topic><topic>SEPARATION PROCESSES</topic><topic>STEROIDS</topic><topic>TRACER TECHNIQUES</topic><topic>VERTEBRATES</topic><topic>VITAMINS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>den Besten, C.</creatorcontrib><creatorcontrib>Peters, M.M.C.G.</creatorcontrib><creatorcontrib>van Bladeren, P.J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>OSTI.GOV</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>den Besten, C.</au><au>Peters, M.M.C.G.</au><au>van Bladeren, P.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The metabolism of pentachlorobenzene by rat liver microsomes: The nature of the reactive intermediates formed</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>1989-09-29</date><risdate>1989</risdate><volume>163</volume><issue>3</issue><spage>1275</spage><epage>1281</epage><pages>1275-1281</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Metabolism of [
14C]-pentachlorobenzene by liver microsomes from dexamethasone-induced rats results in the formation of pentachlorophenol and 2,3,4,6-tetrachlorphenol as major primary metabolites in a ratio of 4:1, with 2,3,4,5- and 2,3,5,6-tetrachlorophenols as minor metabolites. The unsubstituted carbon atom is thus the favourite site of oxidative attack, but the chlorine substituted positions still play a sizable role. As secondary metabolites both para- and ortho-tetrachlorohydroquinone are formed (1.4 and 0.9 % of total metabolites respectively). During this cytochrome P450-dependent conversion of pentachlorobenzene, 5–15 % of the total amount of metabolites becomes covalently bound to microsomal protein. Ascorbic acid inhibits this binding to a considerable extent, indicating that quinone metabolites play an important role in the binding. However, complete inhibition was never reached by ascorbic acid, nor by glutathione, suggesting that other reactive intermediates, presumably epoxides, are also responsible for covalent binding.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>2675838</pmid><doi>10.1016/0006-291X(89)91116-9</doi><tpages>7</tpages></addata></record> |
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| ispartof | Biochemical and biophysical research communications, 1989-09, Vol.163 (3), p.1275-1281 |
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| language | eng |
| recordid | cdi_osti_scitechconnect_5465343 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 550501 - Metabolism- Tracer Techniques 560300 - Chemicals Metabolism & Toxicology ADRENAL HORMONES ANIMALS AROMATICS ASCORBIC ACID BASIC BIOLOGICAL SCIENCES Biotransformation BODY CARBON 14 COMPOUNDS Carbon Radioisotopes CELL CONSTITUENTS CHLORINATED AROMATIC HYDROCARBONS Chlorobenzenes - metabolism CHROMATOGRAPHY Chromatography, High Pressure Liquid CORTICOSTEROIDS DEXAMETHASONE Dexamethasone - pharmacology DIGESTIVE SYSTEM DRUGS ENZYMES GLANDS GLUCOCORTICOIDS GLUTATHIONE HALOGENATED AROMATIC HYDROCARBONS HYDROXY COMPOUNDS Insecticides - metabolism ISOTOPE APPLICATIONS KETONES LABELLED COMPOUNDS LIQUID COLUMN CHROMATOGRAPHY LIVER Male MAMMALS METABOLISM METABOLITES MICROSOMES Microsomes, Liver - drug effects Microsomes, Liver - metabolism MIXED-FUNCTION OXIDASES ORGANIC CHLORINE COMPOUNDS ORGANIC COMPOUNDS ORGANIC HALOGEN COMPOUNDS ORGANOIDS ORGANS OXIDOREDUCTASES OXYGENASES PEPTIDES POLYPEPTIDES PREGNANES PROTEINS RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT Radioisotope Dilution Technique RADIOPROTECTIVE SUBSTANCES RATS Rats, Inbred Strains RIBOSOMES RODENTS SEPARATION PROCESSES STEROIDS TRACER TECHNIQUES VERTEBRATES VITAMINS |
| title | The metabolism of pentachlorobenzene by rat liver microsomes: The nature of the reactive intermediates formed |
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