Exposure to benzo[a]pyrene of hepatic cytochrome P450 reductase null (HRN) and P450 reductase conditional null (RCN) mice

TY - JOUR

T1 - Exposure to benzo[a]pyrene of hepatic cytochrome P450 reductase null (HRN) and P450 reductase conditional null (RCN) mice

T2 - detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and P-postlabelling

A1 - Arlt,Volker M.

A1 - Poirier,Miriam C.

A1 - Sykes,Sarah E.

A1 - John,Kaarthik

A1 - Moserova,Michaela

A1 - Stiborova,Marie

A1 - Wolf,C. Roland

A1 - Henderson,Colin J.

A1 - Phillips,David H.

AU - Arlt,Volker M.

AU - Poirier,Miriam C.

AU - Sykes,Sarah E.

AU - John,Kaarthik

AU - Moserova,Michaela

AU - Stiborova,Marie

AU - Wolf,C. Roland

AU - Henderson,Colin J.

AU - Phillips,David H.

PY - 2012

Y1 - 2012

N2 - 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/kgbody 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 in hepatic microsomes of HRN relative to WT mice suggests that cytochrome b may modulate the P450-mediated bioactivation of BaP in HRN mice, partially substituting the function of Por. © 2012 Elsevier Ireland Ltd.

AB - 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/kgbody 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 in hepatic microsomes of HRN relative to WT mice suggests that cytochrome b may modulate the P450-mediated bioactivation of BaP in HRN mice, partially substituting the function of Por. © 2012 Elsevier Ireland Ltd.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864487999&md5=a8b81aa02f6a7448dc82d967a4744191

U2 - 10.1016/j.toxlet.2012.06.016

DO - 10.1016/j.toxlet.2012.06.016

M1 - Article

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

IS - 2

VL - 213

SP - 160

EP - 166

ER -