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

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• 作者：Robert J. Turesky ; Dmitri Konorev ; Xiaoyu Fan ; Yijin Tang ; Lihua Yao ; Xinxin Ding ; Fang Xie ; Yi Zhu ; Qing-Yu Zhang
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：December 21, 2015
• 年：2015
• 卷：28
• 期：12
• 页码：2400-2410
• 全文大小：554K
• ISSN：1520-5010

文摘

2-Amino-9H-pyrido[2,3-b]indole (A伪C), 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-A伪C). We evaluated the roles of P450 expressed in the liver and intestine to bioactivate A伪C 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 A伪C, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (A伪C-3-OSO₃H), and N²-(尾-1-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (A伪C-N²-Glu) with animals dosed by gavage with A伪C (13.6 mg/kg). The uptake of A伪C was rapid with no difference in the plasma half-lives (t_1/2) of A伪C, A伪C-3-OSO₃H, and A伪C-N²-Glu among mouse models. The maximal plasma concentrations (C_max) and the areas under concentration鈥搕ime curve (AUC_0鈥?4h) of A伪C and A伪C-N²-Glu were 4鈥?4-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 C_max and AUC_0鈥?4h of A伪C-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 A伪C dose (1.36 mg kg^鈥?). dG-C8-A伪C was detected at similar levels in the livers of all three mouse models at the high A伪C dose; levels of dG-C8-A伪C 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 A伪C dose, dG-C8-A伪C occurred at 鈭?0% 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 A伪C, but other hepatic or extrahepatic enzymes contribute to the bioactivation of A伪C. P450s expressed in the intestine do not appreciably contribute to bioactivation of A伪C in mice.