The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mutagenesis

doi:10.1007/s00204-012-0891-6

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	The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mutagenesis
	Luan, Yang 5; Xing, Guozhen 5; Qi, Xinming5 ; Wu, Mengjun 4,5; Li, Chenggang 4,5; Yao, Jun 4,5; Gong, Likun5 ; Nohmi, Takehiko 1; Gu, Jun 2,3; Zhou, Wanhong 6
刊名	ARCHIVES OF TOXICOLOGY
	2012-11
卷号	86 期号:11 页码:1753-1761
关键词	Hepatic P450 gpt delta mouse Gene mutation assay, NNK
ISSN号	0340-5761
DOI	10.1007/s00204-012-0891-6
文献子类	Article
英文摘要	The cytochrome P450 (P450 or CYP) is involved in both detoxification and metabolic activation of many carcinogens. In order to identify the role of hepatic P450 in the mutagenesis of genotoxic carcinogens, we generated a novel hepatic P450 reductase null (HRN) gpt delta mouse model, which lacks functional hepatic P450 on a gpt delta mouse background. In this study, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was used to treat HRN gpt delta mice and control littermates. Gene mutations in the liver and lungs were detected, and mutation spectra were analyzed. Pharmacokinetic analyses were performed, and tissue levels of NNK and metabolite were determined. NNK-induced mutant frequencies (MFs) were equivalent to spontaneous MFs in the liver, but increased more than 3 times in the lungs of HRN gpt delta mice compared to control mice. NNK-induced mutation spectra showed no difference between HRN gpt delta mice and control littermates. Toxicokinetic studies revealed reduced clearance of NNK with elevated tissue concentrations in HRN gpt delta mice. To our knowledge, these are the first data demonstrating that NNK cannot induce mutagenesis in the liver without P450 metabolic activation, but can induce mutagenesis in lungs by a hepatic P450-independent mechanism. Moreover, our data show that hepatic P450 plays a major role in the systemic clearance of NNK, thereby protecting the lungs against NNK-induced mutagenesis. Our model will be useful in establishing the role of hepatic versus extrahepatic P450-mediated mutagenesis, and the relative contributions of P450 compared to other biotransformation enzymes in the genotoxic carcinogens' activation.
资助项目	National Natural Scientific Foundation of China[21077112] ; National Science and the Technology Pillar Program[2008ZX09305-007] ; National Science and the Technology Pillar Program[2009ZX09501-033]
WOS关键词	TOBACCO-SPECIFIC CARCINOGEN ; LIVER-SPECIFIC DELETION ; IN-VIVO ; TRANSGENIC MICE ; CYTOCHROME-P450 REDUCTASE ; METABOLIC-ACTIVATION ; DNA-ADDUCTS ; LUNG TUMORIGENESIS ; ARISTOLOCHIC ACID ; MOUSE MODEL
WOS研究方向	Toxicology
语种	英语
出版者	SPRINGER HEIDELBERG
WOS记录号	WOS:000309864400013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277896]
专题	药物安全性评价中心
通讯作者	Luan, Yang
作者单位	1.Natl Inst Hlth Sci, Div Genet & Mutagenesis, Tokyo 1588501, Japan; 2.SUNY Albany, Sch Publ Hlth, Albany, NY 12201 USA; 3.New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA; 4.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Ctr Drug Safety & Evaluat Res, State Key Lab New Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 6.Shanghai Tobacco Grp Co Ltd, Shanghai 200082, Peoples R China
推荐引用方式 GB/T 7714	Luan, Yang,Xing, Guozhen,Qi, Xinming,et al. The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mutagenesis[J]. ARCHIVES OF TOXICOLOGY,2012,86(11):1753-1761.
APA	Luan, Yang.,Xing, Guozhen.,Qi, Xinming.,Wu, Mengjun.,Li, Chenggang.,...&Ren, Jin.(2012).The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mutagenesis.ARCHIVES OF TOXICOLOGY,86(11),1753-1761.
MLA	Luan, Yang,et al."The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mutagenesis".ARCHIVES OF TOXICOLOGY 86.11(2012):1753-1761.