Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats
Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many car...
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| creator | Zordoky, Beshay N.M. Anwar-Mohamed, Anwar Aboutabl, Mona E. El-Kadi, Ayman O.S. |
| description | Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague–Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of
CYP1A1,
CYP1B1,
CYP2C11,
CYP2J3,
CYP4A1,
CYP4A3,
CYP4F1,
CYP4F4, and
EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP ω-hydroxylases:
CYP4A1,
CYP4A3,
CYP4F1, and
CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the
EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity. |
| doi_str_mv | 10.1016/j.taap.2009.09.012 |
| format | Article |
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CYP1A1,
CYP1B1,
CYP2C11,
CYP2J3,
CYP4A1,
CYP4A3,
CYP4F1,
CYP4F4, and
EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP ω-hydroxylases:
CYP4A1,
CYP4A3,
CYP4F1, and
CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the
EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2009.09.012</identifier><identifier>PMID: 19796650</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; ANIMALS ; ANTI-INFECTIVE AGENTS ; ANTIBIOTICS ; Antibiotics, Antineoplastic - toxicity ; ANTINEOPLASTIC DRUGS ; ARACHIDONIC ACID ; Arachidonic Acid - metabolism ; Biological and medical sciences ; BODY ; CARBOXYLIC ACIDS ; Cardiomegaly - enzymology ; Cardiotoxicity ; CARDIOVASCULAR DISEASES ; CARDIOVASCULAR SYSTEM ; CELL CONSTITUENTS ; Cytochrome P-450 Enzyme System - biosynthesis ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P450 ; DISEASES ; DOSES ; DOXORUBICIN ; Doxorubicin - toxicity ; DRUGS ; ENZYMES ; Epoxide Hydrolase ; Epoxide Hydrolases - genetics ; Epoxide Hydrolases - metabolism ; Gene Expression Regulation, Enzymologic - drug effects ; GENES ; HEART ; Heart Diseases - chemically induced ; Heart Diseases - enzymology ; Hydroxyeicosatetraenoic Acids - metabolism ; HYDROXYLASES ; INJECTION ; INTAKE ; INTRAPERITONEAL INJECTION ; Isoenzymes - biosynthesis ; Isoenzymes - genetics ; L-Lactate Dehydrogenase - biosynthesis ; L-Lactate Dehydrogenase - genetics ; Male ; MAMMALS ; Medical sciences ; METABOLISM ; METABOLITES ; MICROSOMES ; Microsomes - drug effects ; Microsomes - enzymology ; MONOCARBOXYLIC ACIDS ; Myocardium - enzymology ; Myocardium - metabolism ; NEOPLASMS ; ORGANIC ACIDS ; ORGANIC COMPOUNDS ; ORGANS ; OXIDOREDUCTASES ; PATHOGENESIS ; PROTEINS ; RATS ; Rats, Sprague-Dawley ; RIBOSOMES ; RODENTS ; TOXICITY ; Toxicology ; VERTEBRATES</subject><ispartof>Toxicology and applied pharmacology, 2010, Vol.242 (1), p.38-46</ispartof><rights>2009 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-df368680dc2e1aa1e50d5f065d647c93b2510ac8b7e87281f4456e0bc4a64b6a3</citedby><cites>FETCH-LOGICAL-c510t-df368680dc2e1aa1e50d5f065d647c93b2510ac8b7e87281f4456e0bc4a64b6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0041008X09004049$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22249752$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19796650$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/21344824$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Zordoky, Beshay N.M.</creatorcontrib><creatorcontrib>Anwar-Mohamed, Anwar</creatorcontrib><creatorcontrib>Aboutabl, Mona E.</creatorcontrib><creatorcontrib>El-Kadi, Ayman O.S.</creatorcontrib><title>Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague–Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of
CYP1A1,
CYP1B1,
CYP2C11,
CYP2J3,
CYP4A1,
CYP4A3,
CYP4F1,
CYP4F4, and
EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP ω-hydroxylases:
CYP4A1,
CYP4A3,
CYP4F1, and
CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the
EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>ANIMALS</subject><subject>ANTI-INFECTIVE AGENTS</subject><subject>ANTIBIOTICS</subject><subject>Antibiotics, Antineoplastic - toxicity</subject><subject>ANTINEOPLASTIC DRUGS</subject><subject>ARACHIDONIC ACID</subject><subject>Arachidonic Acid - metabolism</subject><subject>Biological and medical sciences</subject><subject>BODY</subject><subject>CARBOXYLIC ACIDS</subject><subject>Cardiomegaly - enzymology</subject><subject>Cardiotoxicity</subject><subject>CARDIOVASCULAR DISEASES</subject><subject>CARDIOVASCULAR SYSTEM</subject><subject>CELL CONSTITUENTS</subject><subject>Cytochrome P-450 Enzyme System - biosynthesis</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P450</subject><subject>DISEASES</subject><subject>DOSES</subject><subject>DOXORUBICIN</subject><subject>Doxorubicin - toxicity</subject><subject>DRUGS</subject><subject>ENZYMES</subject><subject>Epoxide Hydrolase</subject><subject>Epoxide Hydrolases - genetics</subject><subject>Epoxide Hydrolases - metabolism</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>GENES</subject><subject>HEART</subject><subject>Heart Diseases - chemically induced</subject><subject>Heart Diseases - enzymology</subject><subject>Hydroxyeicosatetraenoic Acids - metabolism</subject><subject>HYDROXYLASES</subject><subject>INJECTION</subject><subject>INTAKE</subject><subject>INTRAPERITONEAL INJECTION</subject><subject>Isoenzymes - biosynthesis</subject><subject>Isoenzymes - genetics</subject><subject>L-Lactate Dehydrogenase - biosynthesis</subject><subject>L-Lactate Dehydrogenase - genetics</subject><subject>Male</subject><subject>MAMMALS</subject><subject>Medical sciences</subject><subject>METABOLISM</subject><subject>METABOLITES</subject><subject>MICROSOMES</subject><subject>Microsomes - drug effects</subject><subject>Microsomes - enzymology</subject><subject>MONOCARBOXYLIC ACIDS</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - metabolism</subject><subject>NEOPLASMS</subject><subject>ORGANIC ACIDS</subject><subject>ORGANIC COMPOUNDS</subject><subject>ORGANS</subject><subject>OXIDOREDUCTASES</subject><subject>PATHOGENESIS</subject><subject>PROTEINS</subject><subject>RATS</subject><subject>Rats, Sprague-Dawley</subject><subject>RIBOSOMES</subject><subject>RODENTS</subject><subject>TOXICITY</subject><subject>Toxicology</subject><subject>VERTEBRATES</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV-r1DAQxYMo3vXqF_BBAqJvXZM0TVvw5XLxH1zQBwXfynQyZbO0zZqksvvtTemib8LAMOE3hzk5jL2UYi-FNO-O-wRw2ish2v1aUj1iOylaU4iyLB-znRBaFkI0P2_YsxiPIoNay6fsRrZ1a0wldizc4ZKIW3_2YekdupkjBOt88uc8pQuHMVGI2ysgx0vyeAh-Iv5NV4LT-RQoRudnDrPlEAAPzvrZIQd0lk-UoPejixPP2gFSfM6eDDBGenHtt-zHxw_f7z8XD18_fbm_eyiwkiIVdihNYxphUZEEkFQJWw3CVNboGtuyVxkDbPqamlo1ctC6MiR61GB0b6C8Za83XR-T62I2Q3hAP8-EqVOy1LpROlNvN-oU_K-FYuomF5HGEWbyS8yglMJok0G1gRh8jIGG7hTcBOHSSdGteXTHbs2jW_Po1pIqL726qi_9RPbfyjWADLy5AhARxiHAjC7-5ZRSuq2rVej9xlH-sd-OwmqIZiTrwurHeve_O_4AnAqp6Q</recordid><startdate>2010</startdate><enddate>2010</enddate><creator>Zordoky, Beshay N.M.</creator><creator>Anwar-Mohamed, Anwar</creator><creator>Aboutabl, Mona E.</creator><creator>El-Kadi, Ayman O.S.</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>7ST</scope><scope>7U7</scope><scope>C1K</scope><scope>SOI</scope><scope>OTOTI</scope></search><sort><creationdate>2010</creationdate><title>Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats</title><author>Zordoky, Beshay N.M. ; Anwar-Mohamed, Anwar ; Aboutabl, Mona E. ; El-Kadi, Ayman O.S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-df368680dc2e1aa1e50d5f065d647c93b2510ac8b7e87281f4456e0bc4a64b6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>ANIMALS</topic><topic>ANTI-INFECTIVE AGENTS</topic><topic>ANTIBIOTICS</topic><topic>Antibiotics, Antineoplastic - toxicity</topic><topic>ANTINEOPLASTIC DRUGS</topic><topic>ARACHIDONIC ACID</topic><topic>Arachidonic Acid - metabolism</topic><topic>Biological and medical sciences</topic><topic>BODY</topic><topic>CARBOXYLIC ACIDS</topic><topic>Cardiomegaly - enzymology</topic><topic>Cardiotoxicity</topic><topic>CARDIOVASCULAR DISEASES</topic><topic>CARDIOVASCULAR SYSTEM</topic><topic>CELL CONSTITUENTS</topic><topic>Cytochrome P-450 Enzyme System - biosynthesis</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P450</topic><topic>DISEASES</topic><topic>DOSES</topic><topic>DOXORUBICIN</topic><topic>Doxorubicin - toxicity</topic><topic>DRUGS</topic><topic>ENZYMES</topic><topic>Epoxide Hydrolase</topic><topic>Epoxide Hydrolases - genetics</topic><topic>Epoxide Hydrolases - metabolism</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>GENES</topic><topic>HEART</topic><topic>Heart Diseases - chemically induced</topic><topic>Heart Diseases - enzymology</topic><topic>Hydroxyeicosatetraenoic Acids - metabolism</topic><topic>HYDROXYLASES</topic><topic>INJECTION</topic><topic>INTAKE</topic><topic>INTRAPERITONEAL INJECTION</topic><topic>Isoenzymes - biosynthesis</topic><topic>Isoenzymes - genetics</topic><topic>L-Lactate Dehydrogenase - biosynthesis</topic><topic>L-Lactate Dehydrogenase - genetics</topic><topic>Male</topic><topic>MAMMALS</topic><topic>Medical sciences</topic><topic>METABOLISM</topic><topic>METABOLITES</topic><topic>MICROSOMES</topic><topic>Microsomes - drug effects</topic><topic>Microsomes - enzymology</topic><topic>MONOCARBOXYLIC ACIDS</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - metabolism</topic><topic>NEOPLASMS</topic><topic>ORGANIC ACIDS</topic><topic>ORGANIC COMPOUNDS</topic><topic>ORGANS</topic><topic>OXIDOREDUCTASES</topic><topic>PATHOGENESIS</topic><topic>PROTEINS</topic><topic>RATS</topic><topic>Rats, Sprague-Dawley</topic><topic>RIBOSOMES</topic><topic>RODENTS</topic><topic>TOXICITY</topic><topic>Toxicology</topic><topic>VERTEBRATES</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zordoky, Beshay N.M.</creatorcontrib><creatorcontrib>Anwar-Mohamed, Anwar</creatorcontrib><creatorcontrib>Aboutabl, Mona E.</creatorcontrib><creatorcontrib>El-Kadi, Ayman O.S.</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>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><collection>OSTI.GOV</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zordoky, Beshay N.M.</au><au>Anwar-Mohamed, Anwar</au><au>Aboutabl, Mona E.</au><au>El-Kadi, Ayman O.S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2010</date><risdate>2010</risdate><volume>242</volume><issue>1</issue><spage>38</spage><epage>46</epage><pages>38-46</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague–Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of
CYP1A1,
CYP1B1,
CYP2C11,
CYP2J3,
CYP4A1,
CYP4A3,
CYP4F1,
CYP4F4, and
EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP ω-hydroxylases:
CYP4A1,
CYP4A3,
CYP4F1, and
CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the
EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>19796650</pmid><doi>10.1016/j.taap.2009.09.012</doi><tpages>9</tpages></addata></record> |
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| ispartof | Toxicology and applied pharmacology, 2010, Vol.242 (1), p.38-46 |
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| language | eng |
| recordid | cdi_osti_scitechconnect_21344824 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 60 APPLIED LIFE SCIENCES ANIMALS ANTI-INFECTIVE AGENTS ANTIBIOTICS Antibiotics, Antineoplastic - toxicity ANTINEOPLASTIC DRUGS ARACHIDONIC ACID Arachidonic Acid - metabolism Biological and medical sciences BODY CARBOXYLIC ACIDS Cardiomegaly - enzymology Cardiotoxicity CARDIOVASCULAR DISEASES CARDIOVASCULAR SYSTEM CELL CONSTITUENTS Cytochrome P-450 Enzyme System - biosynthesis Cytochrome P-450 Enzyme System - genetics Cytochrome P450 DISEASES DOSES DOXORUBICIN Doxorubicin - toxicity DRUGS ENZYMES Epoxide Hydrolase Epoxide Hydrolases - genetics Epoxide Hydrolases - metabolism Gene Expression Regulation, Enzymologic - drug effects GENES HEART Heart Diseases - chemically induced Heart Diseases - enzymology Hydroxyeicosatetraenoic Acids - metabolism HYDROXYLASES INJECTION INTAKE INTRAPERITONEAL INJECTION Isoenzymes - biosynthesis Isoenzymes - genetics L-Lactate Dehydrogenase - biosynthesis L-Lactate Dehydrogenase - genetics Male MAMMALS Medical sciences METABOLISM METABOLITES MICROSOMES Microsomes - drug effects Microsomes - enzymology MONOCARBOXYLIC ACIDS Myocardium - enzymology Myocardium - metabolism NEOPLASMS ORGANIC ACIDS ORGANIC COMPOUNDS ORGANS OXIDOREDUCTASES PATHOGENESIS PROTEINS RATS Rats, Sprague-Dawley RIBOSOMES RODENTS TOXICITY Toxicology VERTEBRATES |
| title | Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats |
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