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.
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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.
Issue Date
2012-09-03
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Show full item recordAbstract
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):160-166Journal
Toxicology LettersPubMed ID
22759596Additional Links
http://www.sciencedirect.com/science/article/pii/S0378427412011873Type
ArticleLanguage
enISSN
1879-3169Sponsors
This study was supported by Cancer Research UK and ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility) European Union Network of Excellence.ae974a485f413a2113503eed53cd6c53
10.1016/j.toxlet.2012.06.016
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