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Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice

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Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice. / Arlt, Volker M.; Singh, Rajinder; Stiborova, Marie; da Costa, Goncalo Gamboa; Frei, Eva; Evans, James D.; Farmer, Peter B.; Wolf, C. Roland; Henderson, Colin J.; Phillips, David H.

In: Drug Metabolism and Disposition, Vol. 39, No. 12, 12.2011, p. 2169-2173.

Research output: Contribution to journalArticle

Harvard

Arlt, VM, Singh, R, Stiborova, M, da Costa, GG, Frei, E, Evans, JD, Farmer, PB, Wolf, CR, Henderson, CJ & Phillips, DH 2011, 'Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice' Drug Metabolism and Disposition, vol 39, no. 12, pp. 2169-2173., 10.1124/dmd.111.041343

APA

Arlt, V. M., Singh, R., Stiborova, M., da Costa, G. G., Frei, E., Evans, J. D., ... Phillips, D. H. (2011). Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice. Drug Metabolism and Disposition, 39(12), 2169-2173. 10.1124/dmd.111.041343

Vancouver

Arlt VM, Singh R, Stiborova M, da Costa GG, Frei E, Evans JD et al. Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice. Drug Metabolism and Disposition. 2011 Dec;39(12):2169-2173. Available from: 10.1124/dmd.111.041343

Author

Arlt, Volker M.; Singh, Rajinder; Stiborova, Marie; da Costa, Goncalo Gamboa; Frei, Eva; Evans, James D.; Farmer, Peter B.; Wolf, C. Roland; Henderson, Colin J.; Phillips, David H. / Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice.

In: Drug Metabolism and Disposition, Vol. 39, No. 12, 12.2011, p. 2169-2173.

Research output: Contribution to journalArticle

Bibtex - Download

@article{cf996470891a4bcdb1aba3c66a9c69c0,
title = "Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice",
author = "Arlt, {Volker M.} and Rajinder Singh and Marie Stiborova and {da Costa}, {Goncalo Gamboa} and Eva Frei and Evans, {James D.} and Farmer, {Peter B.} and Wolf, {C. Roland} and Henderson, {Colin J.} and Phillips, {David H.}",
year = "2011",
doi = "10.1124/dmd.111.041343",
volume = "39",
number = "12",
pages = "2169--2173",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 reductase conditional null mice

A1 - Arlt,Volker M.

A1 - Singh,Rajinder

A1 - Stiborova,Marie

A1 - da Costa,Goncalo Gamboa

A1 - Frei,Eva

A1 - Evans,James D.

A1 - Farmer,Peter B.

A1 - Wolf,C. Roland

A1 - Henderson,Colin J.

A1 - Phillips,David H.

AU - Arlt,Volker M.

AU - Singh,Rajinder

AU - Stiborova,Marie

AU - da Costa,Goncalo Gamboa

AU - Frei,Eva

AU - Evans,James D.

AU - Farmer,Peter B.

AU - Wolf,C. Roland

AU - Henderson,Colin J.

AU - Phillips,David H.

PY - 2011/12

Y1 - 2011/12

N2 - <p>2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/10(8) deoxynucleosides), whereas adduct levels in liver were similar to 3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average similar to 2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was similar to 8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.</p>

AB - <p>2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/10(8) deoxynucleosides), whereas adduct levels in liver were similar to 3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average similar to 2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was similar to 8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.</p>

U2 - 10.1124/dmd.111.041343

DO - 10.1124/dmd.111.041343

M1 - Article

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 12

VL - 39

SP - 2169

EP - 2173

ER -

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