Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: Evidence for a metabolism-independent intervention
A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of...
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| Veröffentlicht in: | Toxicology and applied pharmacology 1988-08, Vol.95 (1), p.24-31 |
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| creator | Kerger, Brent D. Roberts, Stephen M. Hinson, Jack A. Gandy, Jay Harbison, Raymond D. James, Robert C. |
| description | A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured
in vivo failed to alter the
in vitro metabolism of bromobenzene to its
ortho- and
para-phenolic metabolites. It is believed that
para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that
ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation. |
| doi_str_mv | 10.1016/S0041-008X(88)80004-8 |
| format | Article |
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in vivo failed to alter the
in vitro metabolism of bromobenzene to its
ortho- and
para-phenolic metabolites. It is believed that
para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that
ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/S0041-008X(88)80004-8</identifier><identifier>PMID: 2901149</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>San Diego, CA: Elsevier Inc</publisher><subject>Adrenergic alpha-Antagonists - pharmacology ; Animals ; Biological and medical sciences ; Biotransformation - drug effects ; Bromobenzenes - antagonists & inhibitors ; Bromobenzenes - blood ; Bromobenzenes - metabolism ; Chemical and Drug Induced Liver Injury ; Chemical and industrial products toxicology. Toxic occupational diseases ; In Vitro Techniques ; Liver - metabolism ; Liver Diseases - metabolism ; Liver Diseases - prevention & control ; Male ; Medical sciences ; Mice ; Microsomes, Liver - metabolism ; Phentolamine - blood ; Phentolamine - metabolism ; Phentolamine - pharmacology ; Toxicology ; Various organic compounds</subject><ispartof>Toxicology and applied pharmacology, 1988-08, Vol.95 (1), p.24-31</ispartof><rights>1988 Academic Press, Inc. All rights reserved</rights><rights>1989 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-b1024803e02645e020e2ff3016af72bf4a8424d8c474caf4c08be952aff107533</citedby><cites>FETCH-LOGICAL-c420t-b1024803e02645e020e2ff3016af72bf4a8424d8c474caf4c08be952aff107533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0041-008X(88)80004-8$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7161201$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2901149$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kerger, Brent D.</creatorcontrib><creatorcontrib>Roberts, Stephen M.</creatorcontrib><creatorcontrib>Hinson, Jack A.</creatorcontrib><creatorcontrib>Gandy, Jay</creatorcontrib><creatorcontrib>Harbison, Raymond D.</creatorcontrib><creatorcontrib>James, Robert C.</creatorcontrib><title>Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: Evidence for a metabolism-independent intervention</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured
in vivo failed to alter the
in vitro metabolism of bromobenzene to its
ortho- and
para-phenolic metabolites. It is believed that
para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that
ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.</description><subject>Adrenergic alpha-Antagonists - pharmacology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biotransformation - drug effects</subject><subject>Bromobenzenes - antagonists & inhibitors</subject><subject>Bromobenzenes - blood</subject><subject>Bromobenzenes - metabolism</subject><subject>Chemical and Drug Induced Liver Injury</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>In Vitro Techniques</subject><subject>Liver - metabolism</subject><subject>Liver Diseases - metabolism</subject><subject>Liver Diseases - prevention & control</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>Phentolamine - blood</subject><subject>Phentolamine - metabolism</subject><subject>Phentolamine - pharmacology</subject><subject>Toxicology</subject><subject>Various organic compounds</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1988</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEFvFCEUx4nR1G31IzThYIwexj4YZpbx0jRNqyZNeqgm3gjDPCxmBkZgNm4_vWx3s1cvD8j7vT_wI-ScwScGrL14ABCsApA_P0j5UUI5VvIFWTHo2grqun5JVkfkNTlN6XdhOiHYCTnhHTAmuhVZrnzWv4J3aaLB0j6GKfTon9Bj5fywGBzoI846hxz-OuPylvZbOj-iz2HUk_P4md5s3IDeILUhUk0nzLoPY0ncJeCMpfhMnc8YN2Xngn9DXlk9Jnx7WM_Ij9ub79dfq7v7L9-ur-4qIzjkqmfAhYQagbeiKRWQW1uX32u75r0VWgouBmnEWhhthQHZY9dwbS2DdVPXZ-T9PneO4c-CKavJJYPjqD2GJSnWsJp3XVvAZg-aGFKKaNUc3aTjVjFQO93qWbfauVRSqmfdSpa588MFSz_hcJw6-C39d4e-TkaPNmpvXDpia9YyDqxgl3sMi4yNw6iScTulg4toshqC-89D_gGGj56e</recordid><startdate>19880801</startdate><enddate>19880801</enddate><creator>Kerger, Brent D.</creator><creator>Roberts, Stephen M.</creator><creator>Hinson, Jack A.</creator><creator>Gandy, Jay</creator><creator>Harbison, Raymond D.</creator><creator>James, Robert C.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</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>7U7</scope><scope>C1K</scope></search><sort><creationdate>19880801</creationdate><title>Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: Evidence for a metabolism-independent intervention</title><author>Kerger, Brent D. ; Roberts, Stephen M. ; Hinson, Jack A. ; Gandy, Jay ; Harbison, Raymond D. ; James, Robert C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-b1024803e02645e020e2ff3016af72bf4a8424d8c474caf4c08be952aff107533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1988</creationdate><topic>Adrenergic alpha-Antagonists - pharmacology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biotransformation - drug effects</topic><topic>Bromobenzenes - antagonists & inhibitors</topic><topic>Bromobenzenes - blood</topic><topic>Bromobenzenes - metabolism</topic><topic>Chemical and Drug Induced Liver Injury</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>In Vitro Techniques</topic><topic>Liver - metabolism</topic><topic>Liver Diseases - metabolism</topic><topic>Liver Diseases - prevention & control</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Phentolamine - blood</topic><topic>Phentolamine - metabolism</topic><topic>Phentolamine - pharmacology</topic><topic>Toxicology</topic><topic>Various organic compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kerger, Brent D.</creatorcontrib><creatorcontrib>Roberts, Stephen M.</creatorcontrib><creatorcontrib>Hinson, Jack A.</creatorcontrib><creatorcontrib>Gandy, Jay</creatorcontrib><creatorcontrib>Harbison, Raymond D.</creatorcontrib><creatorcontrib>James, Robert C.</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kerger, Brent D.</au><au>Roberts, Stephen M.</au><au>Hinson, Jack A.</au><au>Gandy, Jay</au><au>Harbison, Raymond D.</au><au>James, Robert C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: Evidence for a metabolism-independent intervention</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>1988-08-01</date><risdate>1988</risdate><volume>95</volume><issue>1</issue><spage>24</spage><epage>31</epage><pages>24-31</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured
in vivo failed to alter the
in vitro metabolism of bromobenzene to its
ortho- and
para-phenolic metabolites. It is believed that
para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that
ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.</abstract><cop>San Diego, CA</cop><pub>Elsevier Inc</pub><pmid>2901149</pmid><doi>10.1016/S0041-008X(88)80004-8</doi><tpages>8</tpages></addata></record> |
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| subjects | Adrenergic alpha-Antagonists - pharmacology Animals Biological and medical sciences Biotransformation - drug effects Bromobenzenes - antagonists & inhibitors Bromobenzenes - blood Bromobenzenes - metabolism Chemical and Drug Induced Liver Injury Chemical and industrial products toxicology. Toxic occupational diseases In Vitro Techniques Liver - metabolism Liver Diseases - metabolism Liver Diseases - prevention & control Male Medical sciences Mice Microsomes, Liver - metabolism Phentolamine - blood Phentolamine - metabolism Phentolamine - pharmacology Toxicology Various organic compounds |
| title | Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: Evidence for a metabolism-independent intervention |
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