Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling.

2.50
Hdl Handle:
http://hdl.handle.net/10146/269672
Title:
Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling.
Authors:
Arlt, Volker M.; Poirier, Miriam C.; Sykes, Sarah E.; John, Kaarthik; Moserova, Michaela; Stiborova, Marie; Wolf, C. Roland; Henderson, Colin J.; Phillips, David H.
Abstract:
Benzo[a]pyrene (BaP) is a widespread environmental carcinogen activated by cytochrome P450 (P450) enzymes. In Hepatic P450 Reductase Null (HRN) and Reductase Conditional Null (RCN) mice, P450 oxidoreductase (Por) is deleted specifically in hepatocytes, resulting in the loss of essentially all hepatic P450 function. Treatment of HRN mice with a single i.p. or oral dose of BaP (12.5 or 125mg/kg body weight) resulted in higher DNA adduct levels in liver (up to 10-fold) than in wild-type (WT) mice, indicating that hepatic P450s appear to be more important for BaP detoxification in vivo. Similar results were obtained in RCN mice. We tested whether differences between hepatocytes and non-hepatocytes in P450 activity may underlie the increased liver BaP-DNA binding in HRN mice. Cellular localisation by immunohistochemistry of BaP-DNA adducts showed that HRN mice have ample capacity for formation of BaP-DNA adducts in liver, indicating that the metabolic process does not result in the generation of a reactive species different from that formed in WT mice. However, increased protein expression of cytochrome b(5) in hepatic microsomes of HRN relative to WT mice suggests that cytochrome b(5) may modulate the P450-mediated bioactivation of BaP in HRN mice, partially substituting the function of Por.
Citation:
Toxicol. Lett. 2012, 213 (2):160-166
Journal:
Toxicology Letters
Issue Date:
3-Sep-2012
URI:
http://hdl.handle.net/10146/269672
DOI:
10.1016/j.toxlet.2012.06.016
PubMed ID:
22759596
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0378427412011873
Type:
Article
Language:
en
ISSN:
1879-3169
Sponsors:
This study was supported by Cancer Research UK and ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility) European Union Network of Excellence.
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorArlt, Volker M.en_GB
dc.contributor.authorPoirier, Miriam C.en_GB
dc.contributor.authorSykes, Sarah E.en_GB
dc.contributor.authorJohn, Kaarthiken_GB
dc.contributor.authorMoserova, Michaelaen_GB
dc.contributor.authorStiborova, Marieen_GB
dc.contributor.authorWolf, C. Rolanden_GB
dc.contributor.authorHenderson, Colin J.en_GB
dc.contributor.authorPhillips, David H.en_GB
dc.date.accessioned2013-02-15T12:38:01Z-
dc.date.available2013-02-15T12:38:01Z-
dc.date.issued2012-09-03-
dc.identifier.citationToxicol. Lett. 2012, 213 (2):160-166en_GB
dc.identifier.issn1879-3169-
dc.identifier.pmid22759596-
dc.identifier.doi10.1016/j.toxlet.2012.06.016-
dc.identifier.urihttp://hdl.handle.net/10146/269672-
dc.description.abstractBenzo[a]pyrene (BaP) is a widespread environmental carcinogen activated by cytochrome P450 (P450) enzymes. In Hepatic P450 Reductase Null (HRN) and Reductase Conditional Null (RCN) mice, P450 oxidoreductase (Por) is deleted specifically in hepatocytes, resulting in the loss of essentially all hepatic P450 function. Treatment of HRN mice with a single i.p. or oral dose of BaP (12.5 or 125mg/kg body weight) resulted in higher DNA adduct levels in liver (up to 10-fold) than in wild-type (WT) mice, indicating that hepatic P450s appear to be more important for BaP detoxification in vivo. Similar results were obtained in RCN mice. We tested whether differences between hepatocytes and non-hepatocytes in P450 activity may underlie the increased liver BaP-DNA binding in HRN mice. Cellular localisation by immunohistochemistry of BaP-DNA adducts showed that HRN mice have ample capacity for formation of BaP-DNA adducts in liver, indicating that the metabolic process does not result in the generation of a reactive species different from that formed in WT mice. However, increased protein expression of cytochrome b(5) in hepatic microsomes of HRN relative to WT mice suggests that cytochrome b(5) may modulate the P450-mediated bioactivation of BaP in HRN mice, partially substituting the function of Por.en_GB
dc.description.sponsorshipThis study was supported by Cancer Research UK and ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility) European Union Network of Excellence.en_GB
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0378427412011873en_GB
dc.rightsArchived with thanks to Toxicology lettersen_GB
dc.subjectBenzo(a)pyreneen_GB
dc.subjectToxicityen_GB
dc.subjectCytochrome P-450en_GB
dc.subjectDNA damageen_GB
dc.subjectDNA adductsen_GB
dc.subjectHepatocytesen_GB
dc.subjectLiveren_GB
dc.subjectImmunohistochemistryen_GB
dc.subject32P-postlabellingen_GB
dc.subjectAnimalsen_GB
dc.subject.meshAnimals-
dc.subject.meshBenzo(a)pyrene-
dc.subject.meshCytochrome P-450 CYP1A1-
dc.subject.meshCytochromes b5-
dc.subject.meshDNA Adducts-
dc.subject.meshDNA Damage-
dc.subject.meshFemale-
dc.subject.meshHepatocytes-
dc.subject.meshImmunohistochemistry-
dc.subject.meshLiver-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshNADPH-Ferrihemoprotein Reductase-
dc.titleExposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling.en
dc.typeArticleen
dc.identifier.journalToxicology Lettersen_GB

Related articles on PubMed

All Items in ECNIS-NIOM are protected by copyright, with all rights reserved, unless otherwise indicated.