Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls
Identifieur interne : 000F40 ( Istex/Corpus ); précédent : 000F39; suivant : 000F41Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls
Auteurs : Mary Anne Denomme ; Brian Leece ; Angela Li ; Rheal Towner ; Stephen SafeSource :
- Biochemical Pharmacology [ 0006-2952 ] ; 1986.
Abstract
Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.
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DOI: 10.1016/0006-2952(86)90526-5
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls</title><author><name sortKey="Denomme, Mary Anne" sort="Denomme, Mary Anne" uniqKey="Denomme M" first="Mary Anne" last="Denomme">Mary Anne Denomme</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Leece, Brian" sort="Leece, Brian" uniqKey="Leece B" first="Brian" last="Leece">Brian Leece</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Li, Angela" sort="Li, Angela" uniqKey="Li A" first="Angela" last="Li">Angela Li</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Towner, Rheal" sort="Towner, Rheal" uniqKey="Towner R" first="Rheal" last="Towner">Rheal Towner</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Safe, Stephen" sort="Safe, Stephen" uniqKey="Safe S" first="Stephen" last="Safe">Stephen Safe</name><affiliation><mods:affiliation>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</mods:affiliation></affiliation><affiliation><mods:affiliation>‡Author to whom all correspondence should be 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of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Leece, Brian" sort="Leece, Brian" uniqKey="Leece B" first="Brian" last="Leece">Brian Leece</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Li, Angela" sort="Li, Angela" uniqKey="Li A" first="Angela" last="Li">Angela Li</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Towner, Rheal" sort="Towner, Rheal" uniqKey="Towner R" first="Rheal" last="Towner">Rheal Towner</name><affiliation><mods:affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Safe, Stephen" sort="Safe, Stephen" uniqKey="Safe S" first="Stephen" last="Safe">Stephen Safe</name><affiliation><mods:affiliation>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</mods:affiliation></affiliation><affiliation><mods:affiliation>‡Author to whom all correspondence should be addressed.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="ISSN">0006-2952</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1986">1986</date><biblScope unit="volume">35</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="277">277</biblScope><biblScope unit="page" to="282">282</biblScope></imprint><idno type="ISSN">0006-2952</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Mary Anne Denomme</name><affiliations><json:string>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</json:string></affiliations></json:item><json:item><name>Brian Leece</name><affiliations><json:string>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</json:string></affiliations></json:item><json:item><name>Angela Li</name><affiliations><json:string>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</json:string></affiliations></json:item><json:item><name>Rheal Towner</name><affiliations><json:string>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</json:string></affiliations></json:item><json:item><name>Stephen Safe</name><affiliations><json:string>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</json:string><json:string>‡Author to whom all correspondence should be addressed.</json:string></affiliations></json:item></author><articleId><json:string>86905265</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.</abstract><qualityIndicators><score>6.071</score><pdfWordCount>3071</pdfWordCount><pdfCharCount>21298</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>6</pdfPageCount><pdfPageSize>504 x 756 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>339</abstractWordCount><abstractCharCount>2597</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls</title><pii><json:string>0006-2952(86)90526-5</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Biochemical 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type="sub" xml:lang="en">Structure-activity relationships</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>ELSEVIER</p></availability><date>1986</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls</title><title level="a" type="sub" xml:lang="en">Structure-activity relationships</title><author xml:id="author-0000"><persName><forename type="first">Mary Anne</forename><surname>Denomme</surname></persName><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Brian</forename><surname>Leece</surname></persName><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Angela</forename><surname>Li</surname></persName><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Rheal</forename><surname>Towner</surname></persName><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Stephen</forename><surname>Safe</surname></persName><affiliation>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</affiliation><affiliation>‡Author to whom all correspondence should be addressed.</affiliation></author><idno type="istex">C7A11D0BD31CBE09F01BB5EFD1A684F72B5AE097</idno><idno type="DOI">10.1016/0006-2952(86)90526-5</idno><idno type="PII">0006-2952(86)90526-5</idno><idno type="ArticleID">86905265</idno></analytic><monogr><title level="j">Biochemical Pharmacology</title><title level="j" type="abbrev">BCP</title><idno type="pISSN">0006-2952</idno><idno type="PII">S0006-2952(00)X0349-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1986"></date><biblScope unit="volume">35</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="277">277</biblScope><biblScope unit="page" to="282">282</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1986</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.</p></abstract></profileDesc><revisionDesc><change when="1986">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/C7A11D0BD31CBE09F01BB5EFD1A684F72B5AE097/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: tail"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>BCP</jid><aid>86905265</aid><ce:pii>0006-2952(86)90526-5</ce:pii><ce:doi>10.1016/0006-2952(86)90526-5</ce:doi><ce:copyright type="unknown" year="1986"></ce:copyright></item-info><head><ce:title>Elevation of 2,3,7,8-tetrachlorodibenzo-<ce:italic>p</ce:italic>-dioxin (TCDD) polychlorinated biphenyls</ce:title><ce:subtitle>Structure-activity relationships</ce:subtitle><ce:author-group><ce:author><ce:given-name>Mary Anne</ce:given-name><ce:surname>Denomme</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Brian</ce:given-name><ce:surname>Leece</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Angela</ce:given-name><ce:surname>Li</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Rheal</ce:given-name><ce:surname>Towner</ce:surname><ce:cross-ref refid="AFF1"><ce:sup loc="post">∗</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Stephen</ce:given-name><ce:surname>Safe</ce:surname><ce:cross-ref refid="AFF2"><ce:sup loc="post">†</ce:sup></ce:cross-ref><ce:cross-ref refid="FN1"><ce:sup loc="post">‡</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>∗</ce:label><ce:textfn>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>†</ce:label><ce:textfn>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</ce:textfn></ce:affiliation><ce:footnote id="FN1"><ce:label>‡</ce:label><ce:note-para>Author to whom all correspondence should be addressed.</ce:note-para></ce:footnote></ce:author-group><ce:date-received day="6" month="12" year="1984"></ce:date-received><ce:date-accepted day="28" month="5" year="1985"></ce:date-accepted><ce:abstract class="author"><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para view="all" id="simple-para.0010">Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-<ce:italic>p</ce:italic>-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin <ce:italic>O</ce:italic>-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine <ce:italic>N</ce:italic>-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.</ce:simple-para></ce:abstract-sec></ce:abstract></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Elevation of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) polychlorinated biphenyls</title><subTitle>Structure-activity relationships</subTitle></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Elevation of 2,3,7,8-tetrachlorodibenzo-</title><subTitle>Structure-activity relationships</subTitle></titleInfo><name type="personal"><namePart type="given">Mary Anne</namePart><namePart type="family">Denomme</namePart><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Brian</namePart><namePart type="family">Leece</namePart><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Angela</namePart><namePart type="family">Li</namePart><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rheal</namePart><namePart type="family">Towner</namePart><affiliation>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, Canada, N1G 2W1</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephen</namePart><namePart type="family">Safe</namePart><affiliation>Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, U.S.A.</affiliation><affiliation>‡Author to whom all correspondence should be addressed.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1986</dateIssued><copyrightDate encoding="w3cdtf">1986</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80–110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3′,4,4′-Tetra- and 3,3′,4,4′,5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2′,4,4′,5,5′-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmoles/ kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3′,4,4′,5- and 2,2′,3,4,4′,5-hexachloro-biphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.</abstract><relatedItem type="host"><titleInfo><title>Biochemical Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>BCP</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19860115</dateIssued></originInfo><identifier type="ISSN">0006-2952</identifier><identifier type="PII">S0006-2952(00)X0349-8</identifier><part><date>19860115</date><detail type="volume"><number>35</number><caption>vol.</caption></detail><detail type="issue"><number>2</number><caption>no.</caption></detail><extent unit="issue pages"><start>123</start><end>360</end></extent><extent unit="pages"><start>277</start><end>282</end></extent></part></relatedItem><identifier type="istex">C7A11D0BD31CBE09F01BB5EFD1A684F72B5AE097</identifier><identifier type="DOI">10.1016/0006-2952(86)90526-5</identifier><identifier type="PII">0006-2952(86)90526-5</identifier><identifier type="ArticleID">86905265</identifier><recordInfo><recordContentSource>ELSEVIER</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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