Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species
Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase...
Gespeichert in:
Veröffentlicht in: | Biochemical pharmacology 2001-08, Vol.62 (4), p.461-468 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 468 |
---|---|
container_issue | 4 |
container_start_page | 461 |
container_title | Biochemical pharmacology |
container_volume | 62 |
creator | Bailey, Susan M. Lewis, Alex D. Patterson, Laurence H. Fisher, Geoff R. Knox, Richard J. Workman, Paul |
description | Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase tumour cells and under hypoxic conditions. Here, we used purified rat NADPH: cytochrome P450 reductase to provide additional evidence in support of a role for this enzyme in activation of EO9 to generate free radical and DNA-damaging species. Electron spin resonance spectrometry studies showed that NADPH: cytochrome P450 reductase reduced EO9 to a free radical species, including a drug radical (most likely the semiquinone) and reactive oxygen species. Plasmid DNA experiments showed that reduction of EO9 catalysed by NADPH: cytochrome P450 reductase results in single-strand breaks in DNA. The information obtained may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9 and may be useful in the design of future bioreductive drugs. |
doi_str_mv | 10.1016/S0006-2952(01)00674-8 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_70992165</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006295201006748</els_id><sourcerecordid>70992165</sourcerecordid><originalsourceid>FETCH-LOGICAL-e292t-7cab0a083f12396cbd96e2a937af9cfdb0df14dda88e7a7d13002e94120f63a93</originalsourceid><addsrcrecordid>eNpF0U9vFCEYBnBiNHZb_QgaDsboYRSYGQa8mE1bbZOmbaKeybvwTouZgS2wm_TUry7brnriT34QHh5C3nD2iTMuP_9gjMlG6F58YPxjnQ9do56RBVdDW7elek4W_8gBOcz5926pJH9JDjjvOtX1ckEezsM2TlucMRQaR3q5PLk--0LtfYn2NsUZ6XXXM5rQbWyBjNQHWm6Rgi1-C8XHsDvlg4tTvNv4EAPS0ytNS6RjQqQJnLcwUQiOnlwuqYMZbny4oXmN1mN-RV6MMGV8vR-PyK9vpz-Pz5qLq-_nx8uLBoUWpRksrBgw1Y5ctFraldMSBeh2gFHb0a2YG3nnHCiFAwyOt4wJ1B0XbJRtdUfk_dO961TfibmY2WeL0wQB4yabgWktuOwrfLuHm9WMzqyTnyHdm79fVsG7PYBck40JgvX5v2NSqL6t7OsTw5pq6zGZXPMGi84ntMW46Ks1uy7NY5dmV5Rh3Dx2aVT7BytLj5g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70992165</pqid></control><display><type>article</type><title>Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species</title><source>MEDLINE</source><source>ScienceDirect Journals (5 years ago - present)</source><creator>Bailey, Susan M. ; Lewis, Alex D. ; Patterson, Laurence H. ; Fisher, Geoff R. ; Knox, Richard J. ; Workman, Paul</creator><creatorcontrib>Bailey, Susan M. ; Lewis, Alex D. ; Patterson, Laurence H. ; Fisher, Geoff R. ; Knox, Richard J. ; Workman, Paul</creatorcontrib><description>Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase tumour cells and under hypoxic conditions. Here, we used purified rat NADPH: cytochrome P450 reductase to provide additional evidence in support of a role for this enzyme in activation of EO9 to generate free radical and DNA-damaging species. Electron spin resonance spectrometry studies showed that NADPH: cytochrome P450 reductase reduced EO9 to a free radical species, including a drug radical (most likely the semiquinone) and reactive oxygen species. Plasmid DNA experiments showed that reduction of EO9 catalysed by NADPH: cytochrome P450 reductase results in single-strand breaks in DNA. The information obtained may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9 and may be useful in the design of future bioreductive drugs.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/S0006-2952(01)00674-8</identifier><identifier>PMID: 11448456</identifier><identifier>CODEN: BCPCA6</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Animals ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Aziridines - metabolism ; Aziridines - pharmacology ; Biological and medical sciences ; Bioreductive agents ; Catalysis ; DNA - drug effects ; DNA - metabolism ; DNA Damage ; Drug toxicity and drugs side effects treatment ; Electron Spin Resonance Spectroscopy ; EO9 ; Free Radicals - pharmacology ; Indolequinones ; Indoles - metabolism ; Indoles - pharmacology ; Medical sciences ; Miscellaneous (drug allergy, mutagens, teratogens...) ; NADPH-Ferrihemoprotein Reductase - metabolism ; NADPH: cytochrome P450 reductase ; Pharmacology. Drug treatments ; Rats ; Reduction</subject><ispartof>Biochemical pharmacology, 2001-08, Vol.62 (4), p.461-468</ispartof><rights>2001 Elsevier Science Inc.</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-2952(01)00674-8$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1062853$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11448456$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bailey, Susan M.</creatorcontrib><creatorcontrib>Lewis, Alex D.</creatorcontrib><creatorcontrib>Patterson, Laurence H.</creatorcontrib><creatorcontrib>Fisher, Geoff R.</creatorcontrib><creatorcontrib>Knox, Richard J.</creatorcontrib><creatorcontrib>Workman, Paul</creatorcontrib><title>Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase tumour cells and under hypoxic conditions. Here, we used purified rat NADPH: cytochrome P450 reductase to provide additional evidence in support of a role for this enzyme in activation of EO9 to generate free radical and DNA-damaging species. Electron spin resonance spectrometry studies showed that NADPH: cytochrome P450 reductase reduced EO9 to a free radical species, including a drug radical (most likely the semiquinone) and reactive oxygen species. Plasmid DNA experiments showed that reduction of EO9 catalysed by NADPH: cytochrome P450 reductase results in single-strand breaks in DNA. The information obtained may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9 and may be useful in the design of future bioreductive drugs.</description><subject>Animals</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aziridines - metabolism</subject><subject>Aziridines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bioreductive agents</subject><subject>Catalysis</subject><subject>DNA - drug effects</subject><subject>DNA - metabolism</subject><subject>DNA Damage</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Electron Spin Resonance Spectroscopy</subject><subject>EO9</subject><subject>Free Radicals - pharmacology</subject><subject>Indolequinones</subject><subject>Indoles - metabolism</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Miscellaneous (drug allergy, mutagens, teratogens...)</subject><subject>NADPH-Ferrihemoprotein Reductase - metabolism</subject><subject>NADPH: cytochrome P450 reductase</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Reduction</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0U9vFCEYBnBiNHZb_QgaDsboYRSYGQa8mE1bbZOmbaKeybvwTouZgS2wm_TUry7brnriT34QHh5C3nD2iTMuP_9gjMlG6F58YPxjnQ9do56RBVdDW7elek4W_8gBOcz5926pJH9JDjjvOtX1ckEezsM2TlucMRQaR3q5PLk--0LtfYn2NsUZ6XXXM5rQbWyBjNQHWm6Rgi1-C8XHsDvlg4tTvNv4EAPS0ytNS6RjQqQJnLcwUQiOnlwuqYMZbny4oXmN1mN-RV6MMGV8vR-PyK9vpz-Pz5qLq-_nx8uLBoUWpRksrBgw1Y5ctFraldMSBeh2gFHb0a2YG3nnHCiFAwyOt4wJ1B0XbJRtdUfk_dO961TfibmY2WeL0wQB4yabgWktuOwrfLuHm9WMzqyTnyHdm79fVsG7PYBck40JgvX5v2NSqL6t7OsTw5pq6zGZXPMGi84ntMW46Ks1uy7NY5dmV5Rh3Dx2aVT7BytLj5g</recordid><startdate>20010815</startdate><enddate>20010815</enddate><creator>Bailey, Susan M.</creator><creator>Lewis, Alex D.</creator><creator>Patterson, Laurence H.</creator><creator>Fisher, Geoff R.</creator><creator>Knox, Richard J.</creator><creator>Workman, Paul</creator><general>Elsevier Inc</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20010815</creationdate><title>Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species</title><author>Bailey, Susan M. ; Lewis, Alex D. ; Patterson, Laurence H. ; Fisher, Geoff R. ; Knox, Richard J. ; Workman, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-e292t-7cab0a083f12396cbd96e2a937af9cfdb0df14dda88e7a7d13002e94120f63a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Aziridines - metabolism</topic><topic>Aziridines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bioreductive agents</topic><topic>Catalysis</topic><topic>DNA - drug effects</topic><topic>DNA - metabolism</topic><topic>DNA Damage</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Electron Spin Resonance Spectroscopy</topic><topic>EO9</topic><topic>Free Radicals - pharmacology</topic><topic>Indolequinones</topic><topic>Indoles - metabolism</topic><topic>Indoles - pharmacology</topic><topic>Medical sciences</topic><topic>Miscellaneous (drug allergy, mutagens, teratogens...)</topic><topic>NADPH-Ferrihemoprotein Reductase - metabolism</topic><topic>NADPH: cytochrome P450 reductase</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Reduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bailey, Susan M.</creatorcontrib><creatorcontrib>Lewis, Alex D.</creatorcontrib><creatorcontrib>Patterson, Laurence H.</creatorcontrib><creatorcontrib>Fisher, Geoff R.</creatorcontrib><creatorcontrib>Knox, Richard J.</creatorcontrib><creatorcontrib>Workman, Paul</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>MEDLINE - Academic</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bailey, Susan M.</au><au>Lewis, Alex D.</au><au>Patterson, Laurence H.</au><au>Fisher, Geoff R.</au><au>Knox, Richard J.</au><au>Workman, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2001-08-15</date><risdate>2001</risdate><volume>62</volume><issue>4</issue><spage>461</spage><epage>468</epage><pages>461-468</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><coden>BCPCA6</coden><abstract>Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase tumour cells and under hypoxic conditions. Here, we used purified rat NADPH: cytochrome P450 reductase to provide additional evidence in support of a role for this enzyme in activation of EO9 to generate free radical and DNA-damaging species. Electron spin resonance spectrometry studies showed that NADPH: cytochrome P450 reductase reduced EO9 to a free radical species, including a drug radical (most likely the semiquinone) and reactive oxygen species. Plasmid DNA experiments showed that reduction of EO9 catalysed by NADPH: cytochrome P450 reductase results in single-strand breaks in DNA. The information obtained may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9 and may be useful in the design of future bioreductive drugs.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>11448456</pmid><doi>10.1016/S0006-2952(01)00674-8</doi><tpages>8</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0006-2952 |
ispartof | Biochemical pharmacology, 2001-08, Vol.62 (4), p.461-468 |
issn | 0006-2952 1873-2968 |
language | eng |
recordid | cdi_proquest_miscellaneous_70992165 |
source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
subjects | Animals Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Aziridines - metabolism Aziridines - pharmacology Biological and medical sciences Bioreductive agents Catalysis DNA - drug effects DNA - metabolism DNA Damage Drug toxicity and drugs side effects treatment Electron Spin Resonance Spectroscopy EO9 Free Radicals - pharmacology Indolequinones Indoles - metabolism Indoles - pharmacology Medical sciences Miscellaneous (drug allergy, mutagens, teratogens...) NADPH-Ferrihemoprotein Reductase - metabolism NADPH: cytochrome P450 reductase Pharmacology. Drug treatments Rats Reduction |
title | Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T16%3A29%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Involvement%20of%20NADPH:%20cytochrome%20P450%20reductase%20in%20the%20activation%20of%20indoloquinone%20EO9%20to%20free%20radical%20and%20DNA%20damaging%20species&rft.jtitle=Biochemical%20pharmacology&rft.au=Bailey,%20Susan%20M.&rft.date=2001-08-15&rft.volume=62&rft.issue=4&rft.spage=461&rft.epage=468&rft.pages=461-468&rft.issn=0006-2952&rft.eissn=1873-2968&rft.coden=BCPCA6&rft_id=info:doi/10.1016/S0006-2952(01)00674-8&rft_dat=%3Cproquest_pubme%3E70992165%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=70992165&rft_id=info:pmid/11448456&rft_els_id=S0006295201006748&rfr_iscdi=true |