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
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- 作者：Yang Luan (1)
Guozhen Xing (1)
Xinming Qi (1)
Mengjun Wu (1) (2)
Chenggang Li (1) (2)
Jun Yao (1) (2)
Likun Gong (1)
Takehiko Nohmi (3)
Jun Gu (4) (5)
Wanhong Zhou (6)
Saijing Zheng (6)
Jin Ren (1) - 关键词：Hepatic P450 ; gpt delta mouse ; Gene mutation assay ; NNK
- 刊名：Archives of Toxicology
- 出版年：2012
- 出版时间：November 2012
- 年：2012
- 卷：86
- 期：11
- 页码：1753-1761
- 全文大小：363KB
- 参考文献：1. Arlt VM, Stiborova M, Henderson CJ et al (2005) Environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H:quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols. Cancer Res 65(7):2644-652. doi:10.1158/0008-5472.CAN-04-3544 CrossRef
2. Arlt VM, Stiborova M, Henderson CJ et al (2008) Metabolic activation of benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo: experiments with hepatic cytochrome P450 reductase null mice. Carcinogenesis 29(3):656-65. doi:10.1093/carcin/bgn002 CrossRef
3. Arlt VM, Singh R, Stiborova M et al (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 Metab Dispos 39(12):2169-173. doi:10.1124/dmd.111.041343 CrossRef
4. Baird WM, Hooven LA, Mahadevan B (2005) Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen 45(2-):106-14. doi:10.1002/em.20095 CrossRef
5. Boverhof DR, Chamberlain MP, Elcombe CR et al (2011) Transgenic animal models in toxicology: historical perspectives and future outlook. Toxicol Sci 121(2):207-33. doi:10.1093/toxsci/kfr075 CrossRef
6. Brown PJ, Massey TE (2009) In vivo treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces organ-specific alterations in in vitro repair of DNA pyridyloxobutylation. Mutat Res 663(1-):15-1. doi:10.1016/j.mrfmmm.2008.12.008
7. Cariello NF (1994) Software for the analysis of mutations at the human hprt gene. Mutat Res 312:173-85 CrossRef
8. Cleaver JE (1969) Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proc Natl Acad Sci U S A 63(2):428-35 CrossRef
9. Coon MJ (2005) Cytochrome P450: nature’s most versatile biological catalyst. Annu Rev Pharmacol Toxicol 45:1-5. doi:10.1146/annurev.pharmtox.45.120403.100030 CrossRef
10. Dalton TP, Dieter MZ, Matlib RS et al (2000) Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem Biophys Res Commun 267(1):184-89. doi:10.1006/bbrc.1999.1913 CrossRef
11. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286(5439):487-91 CrossRef
12. Grover PL, Sims P (1968) Enzyme-catalysed reactions of polycyclic hydrocarbons with deoxyribonucleic acid and protein in vitro. Biochem J 110(1):159-60
13. Gu J, Weng Y, Zhang QY et al (2003) Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase. J Biol Chem 278(28):25895-5901. doi:10.1074/jbc.M303125200 CrossRef
14. Gu J, Cui H, Behr M et al (2005) In vivo mechanisms of tissue-selective drug toxicity: effects of liver-specific knockout of the NADPH-cytochrome P450 reductase gene on acetaminophen toxicity in kidney, lung, and nasal mucosa. Mol Pharmacol 67(3):623-30. doi:10.1124/mol.104.007898 CrossRef
15. Gu J, Chen CS, Wei Y et al (2007) A mouse model with liver-specific deletion and global suppression of the NADPH-cytochrome P450 reductase gene: characterization and utility for in vivo studies of cyclophosphamide disposition. J Pharmacol Exp Ther 321(1):9-7. doi:10.1124/jpet.106.118240 CrossRef
16. Hang B (2010) Formation and repair of tobacco carcinogen-derived bulky DNA adducts. J Nucleic Acids 2010:709521. doi:10.4061/2010/709521
17. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11(6):559-03. doi:10.1021/tx980005y CrossRef
18. Hecht SS, Trushin N, Rigotty J et al (1996) Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate. Cancer Epidemiol Biomarkers Prev 5(8):645-52
19. Heddle JA, Dean S, Nohmi T et al (2000) In vivo transgenic mutation assays. Environ Mol Mutagen 35(3):253-59. doi:10.1002/(SICI)1098-2280(2000)35:3<253:AID-EM11>3.0.CO;2-J CrossRef
20. Henderson CJ, Otto DM, Carrie D et al (2003) Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase. J Biol Chem 278(15):13480-3486. doi:10.1074/jbc.M212087200 CrossRef
21. Horiguchi M, Masumura K, Ikehata H et al (1999) UVB-induced gpt mutations in the skin of gpt delta transgenic mice. Environ Mol Mutagen 34(2-):72-9. doi:10.1002/(SICI)1098-2280(1999)34:2/3<72:AID-EM3>3.0.CO;2-8 CrossRef
22. Ikeda M, Masumura K, Sakamoto Y et al (2007) Combined genotoxic effects of radiation and a tobacco-specific nitrosamine in the lung of gpt delta transgenic mice. Mutat Res 626(1-):15-5. doi:10.1016/j.mrgentox.2006.07.003
23. Jalas JR, Hecht SS, Murphy SE (2005) Cytochrome P450 enzymes as catalysts of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco specific carcinogen. Chem Res Toxicol 18(2):95-10. doi:10.1021/tx049847p CrossRef
24. Kaufmann WK (1989) Pathways of human cell post-replication repair. Carcinogenesis 10(1):1-1 CrossRef
25. Lao Y, Villalta PW, Sturla SJ, Wang M, Hecht SS (2006) Quantitation of pyridyloxobutyl DNA adducts of tobacco-specific nitrosamines in rat tissue DNA by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Chem Res Toxicol 19(5):674-82. doi:10.1021/tx050351x CrossRef
26. Levova K, Moserova M, Kotrbova V et al (2011) Role of cytochromes P450 1A1/2 in detoxication and activation of carcinogenic aristolochic acid I: studies with the hepatic NADPH:cytochrome P450 reductase null (HRN) mouse model. Toxicol Sci 121(1):43-6. doi:10.1093/toxsci/kfr050 CrossRef
27. Masumura K, Matsui M, Katoh M et al (1999) Spectra of gpt mutations in ethylnitrosourea-treated and untreated transgenic mice. Environ Mol Mutagen 34(1):1- CrossRef
28. Masumura K, Horiguchi M, Nishikawa A et al (2003) Low dose genotoxicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in gpt delta transgenic mice. Mutat Res 541(1-):91-02
29. Minnick DT, Gerson SL, Dumenco LL, Veigl ML, Sedwick WD (1993) Specificity of bischloroethylnitrosourea-induced mutation in a Chinese hamster ovary cell line transformed to express human O6-alkylguanine-DNA alkyltransferase. Cancer Res 53(5):997-003
30. Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6(12):947-60. doi:10.1038/nrc2015 CrossRef
31. Nohmi T (2000) [Development of novel genotoxicity assays by genetic engineering methods]. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku(118):1-0
32. Nohmi T, Masumura K (2004) Gpt delta transgenic mouse: a novel approach for molecular dissection of deletion mutations in vivo. Adv Biophys 38:97-21 CrossRef
33. Nohmi T, Masumura K (2005) Molecular nature of intrachromosomal deletions and base substitutions induced by environmental mutagens. Environ Mol Mutagen 45(2-):150-61. doi:10.1002/em.20110 CrossRef
34. Nohmi T, Katoh M, Suzuki H et al (1996) A new transgenic mouse mutagenesis test system using Spi- and 6-thioguanine selections. Environ Mol Mutagen 28(4):465-70. doi:10.1002/(SICI)1098-2280(1996)28:4<465:AID-EM24>3.0.CO;2-C CrossRef
35. Pineau T, Costet P, Puel O et al (1998) Knockout animals in toxicology: assessment of toxin bioactivation pathways using mice deficient in xenobiotic metabolizing enzymes. Toxicol Lett 102-03:459-64 CrossRef
36. Shane BS, Smith-Dunn DL, deBoer JG, Glickman BW, Cunningham ML (2000) Subchronic administration of phenobarbital alters the mutation spectrum of lacI in the livers of Big Blue transgenic mice. Mutat Res 448(1):69-0 CrossRef
37. Singh VK, Ganesh L, Cunningham ML, Shane BS (2001) Comparison of the mutant frequencies and mutation spectra of three non-genotoxic carcinogens, oxazepam, phenobarbital, and Wyeth 14,643, at the lambdacII locus in Big Blue transgenic mice. Biochem Pharmacol 62(6):685-92 CrossRef
38. Smith TJ, Guo ZY, Thomas PE et al (1990) Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes and its inhibition by isothiocyanates. Cancer Res 50(21):6817-822
39. Sturla SJ, Scott J, Lao Y, Hecht SS, Villalta PW (2005) Mass spectrometric analysis of relative levels of pyridyloxobutylation adducts formed in the reaction of DNA with a chemically activated form of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Res Toxicol 18(6):1048-055. doi:10.1021/tx050028u CrossRef
40. Su T, Bao Z, Zhang QY, Smith TJ, Hong JY, Ding X (2000) Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Res 60(18):5074-079
41. Takeuchi H, Saoo K, Yokohira M et al (2003) Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice. Cancer Res 63(22):7581-583
42. Thybaud V, Dean S, Nohmi T et al (2003) In vivo transgenic mutation assays. Mutat Res 540(2):141-51 CrossRef
43. Uno S, Dalton TP, Derkenne S et al (2004) Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. Mol Pharmacol 65(5):1225-237. doi:10.1124/mol.65.5.1225 CrossRef
44. Weng Y, Fang C, Turesky RJ, Behr M, Kaminsky LS, Ding X (2007) Determination of the role of target tissue metabolism in lung carcinogenesis using conditional cytochrome P450 reductase-null mice. Cancer Res 67(16):7825-832. doi:10.1158/0008-5472.CAN-07-1006 CrossRef
45. Wu L, Gu J, Weng Y et al (2003) Conditional knockout of the mouse NADPH-cytochrome p450 reductase gene. Genesis 36(4):177-81. doi:10.1002/gene.10214 CrossRef
46. Xiao Y, Ge M, Xue X et al (2008) Hepatic cytochrome P450?s metabolize aristolochic acid and reduce its kidney toxicity. Kidney Int 73(11):1231-239 CrossRef - 作者单位：Yang Luan (1)
Guozhen Xing (1)
Xinming Qi (1)
Mengjun Wu (1) (2)
Chenggang Li (1) (2)
Jun Yao (1) (2)
Likun Gong (1)
Takehiko Nohmi (3)
Jun Gu (4) (5)
Wanhong Zhou (6)
Saijing Zheng (6)
Jin Ren (1)
1. Center for Drug Safety and Evaluation Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Haike road 501, Shanghai, 201203, China
2. Graduate School of the Chinese Academy of Sciences, Shanghai, 201203, China
3. Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, 158-8501, Japan
4. New York State Department of Health, Wadsworth Center, Albany, NY, 12201-0509, USA
5. School of Public Health, State University of New York at Albany, Albany, NY, 12201-0509, USA
6. Shanghai Tobacco Group Co., Ltd., Shanghai, 200082, China - ISSN：1432-0738
文摘
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.