Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies
The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that CYP2J2 mRNA expression was significantly ( P
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| Veröffentlicht in: | The pharmacogenomics journal 2015-10, Vol.15 (5), p.405-413 |
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| creator | El-Serafi, I Fares, M Abedi-Valugerdi, M Afsharian, P Moshfegh, A Terelius, Y Potácová, Z Hassan, M |
| description | The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that
CYP2J2
mRNA expression was significantly (
P |
| doi_str_mv | 10.1038/tpj.2014.82 |
| format | Article |
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CYP2J2
mRNA expression was significantly (
P
<0.01) higher in 20 patients with hematological malignancies compared with healthy controls.
CYP2J2
expression showed significant upregulation (
P
<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to
CYP2J2
expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 m
M
). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent
K
m
and
V
max
values of 3.7–6.6 m
M
and 2.9–10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs.</description><identifier>ISSN: 1470-269X</identifier><identifier>ISSN: 1473-1150</identifier><identifier>EISSN: 1473-1150</identifier><identifier>DOI: 10.1038/tpj.2014.82</identifier><identifier>PMID: 25601761</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 38/22 ; 38/39 ; 38/77 ; 38/90 ; 692/308/575 ; Adolescent ; Adult ; Biomarkers, Tumor - biosynthesis ; Biomarkers, Tumor - genetics ; Biomedical and Life Sciences ; Biomedicine ; Blood diseases ; Cell survival ; Cell viability ; Child ; Complications and side effects ; Cyclophosphamide ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - adverse effects ; Cytochrome ; Cytochrome P-450 ; Cytochrome P-450 Enzyme System - biosynthesis ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P450 ; Drug metabolism ; Female ; Gene Expression ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Health aspects ; Heart - drug effects ; Hematologic Neoplasms - drug therapy ; Hematologic Neoplasms - genetics ; Hematologic Neoplasms - pathology ; Hematology ; HL-60 Cells ; Human Genetics ; Humans ; Intestine ; Intestines - drug effects ; Intestines - metabolism ; Male ; Medicin och hälsovetenskap ; Metabolism ; Microsomes ; Middle Aged ; Oncology ; Organs ; original-article ; Pharmacotherapy ; Properties ; Psychopharmacology ; Risk factors ; Stem Cell Transplantation ; Stem cells ; Toxicity ; Transplantation ; Urinary bladder ; Urinary Bladder - drug effects ; Urinary Bladder - metabolism</subject><ispartof>The pharmacogenomics journal, 2015-10, Vol.15 (5), p.405-413</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c570t-fcb248e4579ca32fb92aab5209f338d25af2b69034d1acc941c085375a6101c23</citedby><cites>FETCH-LOGICAL-c570t-fcb248e4579ca32fb92aab5209f338d25af2b69034d1acc941c085375a6101c23</cites><orcidid>0000-0003-1927-5859</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25601761$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:132069529$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>El-Serafi, I</creatorcontrib><creatorcontrib>Fares, M</creatorcontrib><creatorcontrib>Abedi-Valugerdi, M</creatorcontrib><creatorcontrib>Afsharian, P</creatorcontrib><creatorcontrib>Moshfegh, A</creatorcontrib><creatorcontrib>Terelius, Y</creatorcontrib><creatorcontrib>Potácová, Z</creatorcontrib><creatorcontrib>Hassan, M</creatorcontrib><title>Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies</title><title>The pharmacogenomics journal</title><addtitle>Pharmacogenomics J</addtitle><addtitle>Pharmacogenomics J</addtitle><description>The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that
CYP2J2
mRNA expression was significantly (
P
<0.01) higher in 20 patients with hematological malignancies compared with healthy controls.
CYP2J2
expression showed significant upregulation (
P
<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to
CYP2J2
expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 m
M
). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent
K
m
and
V
max
values of 3.7–6.6 m
M
and 2.9–10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs.</description><subject>13/106</subject><subject>38/22</subject><subject>38/39</subject><subject>38/77</subject><subject>38/90</subject><subject>692/308/575</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Biomarkers, Tumor - biosynthesis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood diseases</subject><subject>Cell survival</subject><subject>Cell viability</subject><subject>Child</subject><subject>Complications and side effects</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Cyclophosphamide - adverse effects</subject><subject>Cytochrome</subject><subject>Cytochrome P-450</subject><subject>Cytochrome P-450 Enzyme System - biosynthesis</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P450</subject><subject>Drug metabolism</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Heart - drug effects</subject><subject>Hematologic Neoplasms - drug therapy</subject><subject>Hematologic Neoplasms - genetics</subject><subject>Hematologic Neoplasms - pathology</subject><subject>Hematology</subject><subject>HL-60 Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Intestine</subject><subject>Intestines - drug effects</subject><subject>Intestines - metabolism</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Metabolism</subject><subject>Microsomes</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Organs</subject><subject>original-article</subject><subject>Pharmacotherapy</subject><subject>Properties</subject><subject>Psychopharmacology</subject><subject>Risk factors</subject><subject>Stem Cell Transplantation</subject><subject>Stem cells</subject><subject>Toxicity</subject><subject>Transplantation</subject><subject>Urinary bladder</subject><subject>Urinary Bladder - drug effects</subject><subject>Urinary Bladder - metabolism</subject><issn>1470-269X</issn><issn>1473-1150</issn><issn>1473-1150</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kk1v1DAQhiMEoqVw4o4icUGiWTxjO4mP1YpPVYIDSNwsx3F2vU3sYGeplhM_Hae7bQEV5IOteZ93PB5Plj0FsgBC61fTuFkgAbao8V52DKyiBQAn96_OpMBSfD3KHsW4IQRKqOqH2RHykkBVwnH2c7mbvF4HP5j8E-Mkxw94mqvcmcv8wuxy437skmRdrne69-Pax3GtBtuavLFe6cl-V5P1LleuTbbRT8ZNVvWzOqhwYULe-ZCvzaAm3_uV1UkbVG9XTjltTXycPehUH82Tw36SfXnz-vPyXXH-8e375dl5oXlFpqLTDbLaMF4JrSh2jUClGo5EdJTWLXLVYVMKQlkLSmvBQJOa04qrEghopCdZsc8bL824beQYbKpvJ72y8hC6SCcjOZSIIvHin_wYfHtrujYCRVIKfuV9sfcm8NvWxEkONmrT98oZv40SKkSoKNYsoc__Qjd-G1zqhERK5_8CRv9HzQByBIG31Er1RlrX-SkoPV8tzxgFxrggkKjFHVRarRms9s50NsX_MLzcG3TwMQbT3fQCiJwnUKYJlPMEynou4tmh1G0zmPaGvR65BJweGpsktzLht7fcke8XhWTkJQ</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>El-Serafi, I</creator><creator>Fares, M</creator><creator>Abedi-Valugerdi, M</creator><creator>Afsharian, P</creator><creator>Moshfegh, A</creator><creator>Terelius, Y</creator><creator>Potácová, Z</creator><creator>Hassan, M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>ADTPV</scope><scope>AOWAS</scope><orcidid>https://orcid.org/0000-0003-1927-5859</orcidid></search><sort><creationdate>20151001</creationdate><title>Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies</title><author>El-Serafi, I ; Fares, M ; Abedi-Valugerdi, M ; Afsharian, P ; Moshfegh, A ; Terelius, Y ; Potácová, Z ; Hassan, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c570t-fcb248e4579ca32fb92aab5209f338d25af2b69034d1acc941c085375a6101c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13/106</topic><topic>38/22</topic><topic>38/39</topic><topic>38/77</topic><topic>38/90</topic><topic>692/308/575</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Biomarkers, Tumor - biosynthesis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood diseases</topic><topic>Cell survival</topic><topic>Cell viability</topic><topic>Child</topic><topic>Complications and side effects</topic><topic>Cyclophosphamide</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Cyclophosphamide - adverse effects</topic><topic>Cytochrome</topic><topic>Cytochrome P-450</topic><topic>Cytochrome P-450 Enzyme System - biosynthesis</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P450</topic><topic>Drug metabolism</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Heart - drug effects</topic><topic>Hematologic Neoplasms - drug therapy</topic><topic>Hematologic Neoplasms - genetics</topic><topic>Hematologic Neoplasms - pathology</topic><topic>Hematology</topic><topic>HL-60 Cells</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Intestine</topic><topic>Intestines - drug effects</topic><topic>Intestines - metabolism</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Metabolism</topic><topic>Microsomes</topic><topic>Middle Aged</topic><topic>Oncology</topic><topic>Organs</topic><topic>original-article</topic><topic>Pharmacotherapy</topic><topic>Properties</topic><topic>Psychopharmacology</topic><topic>Risk factors</topic><topic>Stem Cell Transplantation</topic><topic>Stem cells</topic><topic>Toxicity</topic><topic>Transplantation</topic><topic>Urinary bladder</topic><topic>Urinary Bladder - drug effects</topic><topic>Urinary Bladder - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>El-Serafi, I</creatorcontrib><creatorcontrib>Fares, M</creatorcontrib><creatorcontrib>Abedi-Valugerdi, M</creatorcontrib><creatorcontrib>Afsharian, P</creatorcontrib><creatorcontrib>Moshfegh, A</creatorcontrib><creatorcontrib>Terelius, Y</creatorcontrib><creatorcontrib>Potácová, Z</creatorcontrib><creatorcontrib>Hassan, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>The pharmacogenomics journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>El-Serafi, I</au><au>Fares, M</au><au>Abedi-Valugerdi, M</au><au>Afsharian, P</au><au>Moshfegh, A</au><au>Terelius, Y</au><au>Potácová, Z</au><au>Hassan, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies</atitle><jtitle>The pharmacogenomics journal</jtitle><stitle>Pharmacogenomics J</stitle><addtitle>Pharmacogenomics J</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>15</volume><issue>5</issue><spage>405</spage><epage>413</epage><pages>405-413</pages><issn>1470-269X</issn><issn>1473-1150</issn><eissn>1473-1150</eissn><abstract>The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that
CYP2J2
mRNA expression was significantly (
P
<0.01) higher in 20 patients with hematological malignancies compared with healthy controls.
CYP2J2
expression showed significant upregulation (
P
<0.05) during Cy treatment before stem cell transplantation. Cy bioactivation was significantly correlated to
CYP2J2
expression. Studies in HL-60 cells expressing CYP2J2 showed reduced cell viability when incubated with Cy (half maximal inhibitory concentration=3.6 m
M
). Inhibition of CYP2J2 using telmisartan reduced Cy bioactivation by 50% and improved cell survival. Cy incubated with recombinant CYP2J2 microsomes has resulted in apparent
K
m
and
V
max
values of 3.7–6.6 m
M
and 2.9–10.3 pmol/(min·pmol) CYP, respectively. This is the first study demonstrating that CYP2J2 is equally important to CYP2B6 in Cy metabolism. The heart, intestine and urinary bladder express high levels of CYP2J2; local Cy bioactivation may explain Cy-treatment-related toxicities in these organs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25601761</pmid><doi>10.1038/tpj.2014.82</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-1927-5859</orcidid></addata></record> |
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| issn | 1470-269X 1473-1150 1473-1150 |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | 13/106 38/22 38/39 38/77 38/90 692/308/575 Adolescent Adult Biomarkers, Tumor - biosynthesis Biomarkers, Tumor - genetics Biomedical and Life Sciences Biomedicine Blood diseases Cell survival Cell viability Child Complications and side effects Cyclophosphamide Cyclophosphamide - administration & dosage Cyclophosphamide - adverse effects Cytochrome Cytochrome P-450 Cytochrome P-450 Enzyme System - biosynthesis Cytochrome P-450 Enzyme System - genetics Cytochrome P450 Drug metabolism Female Gene Expression Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Health aspects Heart - drug effects Hematologic Neoplasms - drug therapy Hematologic Neoplasms - genetics Hematologic Neoplasms - pathology Hematology HL-60 Cells Human Genetics Humans Intestine Intestines - drug effects Intestines - metabolism Male Medicin och hälsovetenskap Metabolism Microsomes Middle Aged Oncology Organs original-article Pharmacotherapy Properties Psychopharmacology Risk factors Stem Cell Transplantation Stem cells Toxicity Transplantation Urinary bladder Urinary Bladder - drug effects Urinary Bladder - metabolism |
| title | Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies |
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