title: Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice.
abstract: 2-Amino-9H-pyrido[2,3-b]indole (AαC), a carcinogen formed during the combustion of tobacco and cooking of meat, undergoes cytochrome P450 (P450) metabolism to form the DNA adduct N-(deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC). We evaluated the roles of P450 expressed in the liver and intestine to bioactivate AαC by employing male B6 wild-type (WT) mice, liver-specific P450 reductase (Cpr)-null (LCN) mice, and intestinal epithelium-specific Cpr-null (IECN) mice. Pharmacokinetic parameters were determined for AαC, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AαC-3-OSO3H), and N(2)-(β-1-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N(2)-Glu) with animals dosed by gavage with AαC (13.6 mg/kg). The uptake of AαC was rapid with no difference in the plasma half-lives (t1/2) of AαC, AαC-3-OSO3H, and AαC-N(2)-Glu among mouse models. The maximal plasma concentrations (Cmax) and the areas under concentration-time curve (AUC0-24h) of AαC and AαC-N(2)-Glu were 4-24-fold higher in LCN than in WT mice, but they were not different between WT and IECN mice. These findings are consistent with the ablation of hepatic P450 activity in LCN mice. However, the Cmax and AUC0-24h of AαC-3-OSO3H in plasma were not substantially different among the mouse models. Similar pharmacokinetic parameters were obtained with WT and LCN mice treated with a lower AαC dose (1.36 mg kg(-1)). dG-C8-AαC was detected at similar levels in the livers of all three mouse models at the high AαC dose; levels of dG-C8-AαC in colon, bladder, and lung were greater in LCN than in WT mice and were the same in colon of IECN and WT mice. At the low AαC dose, dG-C8-AαC occurred at ∼ 40% lower levels in liver of LCN mouse than in WT mouse liver, but adduct levels remained higher in extrahepatic tissues of LCN mice. Therefore, hepatic P450 plays an important role in detoxication of AαC, but other hepatic or extrahepatic enzymes contribute to the bioactivation of AαC. P450s expressed in the intestine do not appreciably contribute to bioactivation of AαC in mice.
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Konorev
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany , Albany, New York 12201, United States.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fan
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany , Albany, New York 12201, United States.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yao
authors.affiliation: College of Nanoscale Science and Engineering, SUNY Polytechnic Institute , Albany, New York 12203, United States.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany , Albany, New York 12201, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany , Albany, New York 12201, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany , Albany, New York 12201, United States.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002243:Carbolines / Q000097:blood / Q000737:chemistry*; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000737:chemistry*; D008099:Liver / Q000737:chemistry*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency*; D010105:Oxygenases / Q000378:metabolism
chemical_list: D002243:Carbolines; D018736:DNA Adducts; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D009251:NADPH-Ferrihemoprotein Reductase; C017822:2-amino-9H-pyrido(2,3-b)indole