Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:cytochrome P450 reductase null mouse.

2.50
Hdl Handle:
http://hdl.handle.net/10146/38099
Title:
Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:cytochrome P450 reductase null mouse.
Authors:
Stiborova, Marie; Arlt, Volker M.; Henderson, Colin J.; Wolf, C. Roland; Kotrbova, Vera; Moserova, Michaela; Hudecek, Jiri; Phillips, David H.; Frei, Eva
Abstract:
Ellipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by (32)P-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study.
Citation:
Toxicol. Appl. Pharmacol. 2008, 226 (3):318-327
Journal:
Toxicology and Applied Pharmacology
Issue Date:
1-Feb-2008
URI:
http://hdl.handle.net/10146/38099
DOI:
10.1016/j.taap.2007.09.017
PubMed ID:
17976674
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4PRYFTR-3&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=1843694&md5=e8aad53ac08d90514fe122c9fa633b3b
Type:
Article
Language:
en
ISSN:
0041-008X
Sponsors:
This work was supported in part by Grant Agency of the Czech Republic, grant 203/06/0329, Ministry of Education of the Czech Republic, grants MSM0021620808 and 1M4635608802-Center of Targeted Therapeutics and by Cancer Research UK. V.M. Arlt, C.J. Henderson, C.R. Wolf and D.H. Phillips are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorStiborova, Marie-
dc.contributor.authorArlt, Volker M.-
dc.contributor.authorHenderson, Colin J.-
dc.contributor.authorWolf, C. Roland-
dc.contributor.authorKotrbova, Vera-
dc.contributor.authorMoserova, Michaela-
dc.contributor.authorHudecek, Jiri-
dc.contributor.authorPhillips, David H.-
dc.contributor.authorFrei, Eva-
dc.date.accessioned2008-09-24T10:32:52Z-
dc.date.available2008-09-24T10:32:52Z-
dc.date.issued2008-02-01-
dc.identifier.citationToxicol. Appl. Pharmacol. 2008, 226 (3):318-327en
dc.identifier.issn0041-008X-
dc.identifier.pmid17976674-
dc.identifier.doi10.1016/j.taap.2007.09.017-
dc.identifier.urihttp://hdl.handle.net/10146/38099-
dc.description.abstractEllipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by (32)P-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study.en
dc.description.sponsorshipThis work was supported in part by Grant Agency of the Czech Republic, grant 203/06/0329, Ministry of Education of the Czech Republic, grants MSM0021620808 and 1M4635608802-Center of Targeted Therapeutics and by Cancer Research UK. V.M. Arlt, C.J. Henderson, C.R. Wolf and D.H. Phillips are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4PRYFTR-3&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=1843694&md5=e8aad53ac08d90514fe122c9fa633b3ben
dc.subjectAnticancer drugen
dc.subjectEllipticineen
dc.subjectCytochrome P450en
dc.subjectPeroxidaseen
dc.subjectDNA adductsen
dc.subject32P-postlabellingen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCytochrome P-450 CYP1A1-
dc.subject.meshCytochrome P-450 CYP3A-
dc.subject.meshDNA-
dc.subject.meshDNA Adducts-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshEllipticines-
dc.subject.meshGene Silencing-
dc.subject.meshHepatocytes-
dc.subject.meshInjections, Intraperitoneal-
dc.subject.meshIsotope Labeling-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshNADPH-Ferrihemoprotein Reductase-
dc.subject.meshPhosphorus Radioisotopes-
dc.titleRole of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:cytochrome P450 reductase null mouse.en
dc.typeArticleen
dc.identifier.journalToxicology and Applied Pharmacologyen

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