内源性亚硝胺在食管癌一级预防中的作用及意义_West China Medical Journal

Authors：

郑希 , 胡杨 , 袁勇 ,  赵雍凡

Corresponding author：

赵雍凡, Email: zheng.xi@foxmail.com

Keywords：

内源性亚硝胺; 食管癌; 一级预防

DOI：

10.7507/1002-0179.20130615

Video：

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亚硝胺是一类公认的食管癌化学致癌物。它们广泛存在于人类生存环境中（外源性亚硝胺），也可在一定条件下于人体内合成（内源性亚硝胺）。我国通过控制人群外源性亚硝胺暴露的措施，并未使食管癌发病率明显下降，故内源性亚硝胺诱发人类食管癌的作用可能强于外源性亚硝胺。内源性合成是人体亚硝胺的主要来源，且内源性亚硝胺可致人类食管癌，因而减少人体内源性亚硝胺的暴露可成为食管癌一级预防的重要措施。关于内源性亚硝胺与食管癌预防的可能研究方向总结如下：① 减少亚硝胺底物的摄入及形成、抑制亚硝胺合成反应可减少内源性亚硝胺的暴露;② 亚硝胺在体内的吸收过程可能为被动扩散，干预其吸收过程仍存在困难;③ 亚硝胺本身不致突变，其致突变活性决定于其在体内的代谢或诱导产物，故抑制亚硝胺体内代谢活化也可能抑制食管癌的发生。

Citation： 郑希,胡杨,袁勇,赵雍凡. 内源性亚硝胺在食管癌一级预防中的作用及意义. West China Medical Journal, 2013, 28(12): 1945-1948. doi: 10.7507/1002-0179.20130615 Copy

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2.	Jakszyn P, Gonzalez CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence[J]. World J Gastroenterol, 2006, 12(27): 4296-4303.
3.	Mao WM, Zheng WH, Ling ZQ . Epidemiologic risk factors for esophageal cancer development[J]. Asian Pac J Cancer Prev, 2011, 12(10): 2461-2466.
4.	Wilp J, Zwickenpflug W, Richter E. Nitrosation of dietary myosmine as risk factor of human cancer[J]. Food Chem Toxicol, 2002, 40(8): 1223-1228.
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6.	Lijinsky W. Reaction of drugs with nitrous acid as a source of carcinogenic nitrosamines[J]. Cancer Res, 1974, 34(1): 255-258.
7.	Xie TP, Zhao YF, Chen LQ, et al. Long-term exposure to Sodium nitrite and risk of esophageal carcinoma: a cohort study for 30 years[J]. Dis Esophagus, 2011, 24(1): 30-32.
8.	Huang YG, Ji JD, Hou QN. A study on carcinogenesis of endogenous nitrite and nitrosamine, and prevention of cancer[J]. Mutat Res, 1996, 358(1): 7-14.
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12.	Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC[J]. Cancer Lett, 1995, 93(1): 17-48.
13.	Reed PI, Smith PL, Haines K, et al. Effect of cimetidine on gastric juice N-nitrosamine concentration[J]. Lancet, 1981, 2(8246): 553-556.
14.	Ziebarth D, Spiegelhalder B, Bartsch H. N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori[J]. Carcinogenesis, 1997, 18(2): 383-389.
15.	Kapil V, Haydar SM, Pearl V, et al. Physiological role for nitrate-reducing oral bacteria in blood pressure control[J]. Free Radic Biol Med, 2013, 55: 93-100.
16.	Waddell WJ. Critique of dose response in carcinogenesis[J]. Hum Exp Toxicol, 2006, 25(7): 413-436.
17.	Waddell WJ, Fukushima S, Williams GM. Concordance of thresholds for carcinogenicity of N-nitrosodiethylamine[J]. Arch Toxicol, 2006, 80(6): 305-309.
18.	Abrams JA, Gonsalves L, Neugut AI. Diverging trends in the incidence of reflux-related and Helicobacter pylori-related gastric cardia cancer[J]. J Clin Gastroenterol, 2013, 47(4): 322-327.
19.	Silva JF, Bidinotto LT, Furtado KS, et al. Maté attenuates DNA damage and carcinogenesis induced by diethylnitrosamine and thermal injury in rat esophagus[J]. Food Chem Toxicol, 2009, 47(7): 1521-1529.
20.	Maliakal P, Sankpal UT, Basha R, et al. Relevance of drug metabolizing enzyme activity modulation by tea polyphenols in the inhibition of esophageal tumorigenesis[J]. Med Chem, 2011, 7(5): 480-487.
21.	Yang H, Fang J, Jia X, et al. Chemopreventive effects of early-stage and late-stage supplementation of vitamin E and Selenium on esophageal carcinogenesis in rats maintained on a low vitamin E/Selenium diet[J]. Carcinogenesis, 2011, 32(3): 381-388.
22.	Pegg AE, Perry W. Alkylation of nucleic acids and metabolism of small doses of dimethylnitrosamine in the rat[J]. Cancer Res, 1981, 41(8): 3128-3132.
23.	Haorah J, Miller DW, Brand R, et al. Diffusion of dialkylnitrosamines into the rat esophagus as a factor in esophageal carcinogenesis[J]. Carcinogenesis, 1999, 20(5): 825-836.
24.	Lundberg JO, Weitzberg E. Biology of nitrogen oxides in the gastrointestinal tract[J]. Gut, 2013, 62(4): 616-629.
25.	de Castro Junior MA, Kruel CD, Meurer L, et al. Immunohistochemical expression of P53 and Ki-67 in diethylnitrosamine-induced carcinomas esophageal: experimental model[J]. Rev Col Bras Cir, 2010, 37(2): 128-134.
26.	Hebels DG, Briedé JJ, Khampang R, et al. Radical mechanisms in nitrosamine-and nitrosamide-induced whole-genome gene expression modulations in Caco-2 cells[J]. Toxicol Sci, 2010, 116(1): 194-205.
27.	Chen T, Stoner GD. Inducible nitric oxide synthase expression in N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis[J]. Mol Carcinog, 2004, 40(4): 232-240.
28.	Gomez MI, Swann PF, Magee PN. The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Implication for the possible hazard of dimethylnitrosamine in human food[J]. Biochem J, 1977, 164(3): 497-500.
29.	Yang CS, Smith T, Ishizaki, et al. Enzyme mechanisms in the metabolism of nitrosamines[J]. IARC Sci Publ, 1991(105): 265-274.
30.	Huang Q, Stoner G, Resau J, et al. Metabolism of N-nitrosomethyl-n-amylamine by microsomes from human and rat esophagus[J]. Cancer Res, 1992, 52(13): 3547-3551.
31.	Chowdhury G, Calcutt MW, Nagy LD, et al. Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1[J]. Biochemistry, 2012, 51(50): 9995-10007.
32.	Loeppky RN. The mechanism of bioactivation of N-nitrosodiethanolamine[J]. Drug Metab Rev, 1999, 31(1): 175-193.
33.	Chen T, Hwang H, Rose ME, et al. Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun[J]. Cancer Res, 2006, 66(5): 2853-2859.
34.	Stoner GD, Chen T, Kresty LA, et al. Protection against esophageal cancer in rodents with lyophilized berries: potential mechanisms[J]. Nutr Cancer, 2006, 54(1): 33-46.
35.	Stoner GD, Wang LS, Seguin C, et al. Multiple berry types prevent N-nitrosomethylbenzylamine-induced esophageal cancer in rats[J]. Pharm Res, 2010, 27(6): 1138-1145.

1. 　Craddock VM. Aetiology of oesophageal cancer: some operative factors[J]. Eur J Cancer Prev, 1992, 1(2): 89-103.
2. 　Jakszyn P, Gonzalez CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence[J]. World J Gastroenterol, 2006, 12(27): 4296-4303.
3. 　Mao WM, Zheng WH, Ling ZQ . Epidemiologic risk factors for esophageal cancer development[J]. Asian Pac J Cancer Prev, 2011, 12(10): 2461-2466.
4. 　Wilp J, Zwickenpflug W, Richter E. Nitrosation of dietary myosmine as risk factor of human cancer[J]. Food Chem Toxicol, 2002, 40(8): 1223-1228.
5. 　Lambert R, Hainaut P. The multidisciplinary management of gastrointestinal cancer. Epidemiology of oesophagogastric cancer[J]. Best Pract Res Clin Gastroenterol, 2007, 21(6): 921-945.
6. 　Lijinsky W. Reaction of drugs with nitrous acid as a source of carcinogenic nitrosamines[J]. Cancer Res, 1974, 34(1): 255-258.
7. 　Xie TP, Zhao YF, Chen LQ, et al. Long-term exposure to Sodium nitrite and risk of esophageal carcinoma: a cohort study for 30 years[J]. Dis Esophagus, 2011, 24(1): 30-32.
8. 　Huang YG, Ji JD, Hou QN. A study on carcinogenesis of endogenous nitrite and nitrosamine, and prevention of cancer[J]. Mutat Res, 1996, 358(1): 7-14.
9. 　Rostkowska K, Zwierz K, Ró?ański A. Formation and metabolism of N-Nitrosamines[J]. Polish J Envir Stud, 1998, 7(6): 321-325.
10. 　Al Bulushi I, Poole S, Deeth HC, et al. Biogenic amines in fish: roles in intoxication, spoilage, and nitrosamine formation-a review[J]. Crit Rev Food Sci Nutr, 2009, 49(4): 369-377.
11. 　夏登胜, 王松灵. 唾液硝酸盐、亚硝酸盐代谢及其对人体影响的研究[J]. 北京口腔医学, 2005, 13(1): 57-59.
12. 　Mirvish SS. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC[J]. Cancer Lett, 1995, 93(1): 17-48.
13. 　Reed PI, Smith PL, Haines K, et al. Effect of cimetidine on gastric juice N-nitrosamine concentration[J]. Lancet, 1981, 2(8246): 553-556.
14. 　Ziebarth D, Spiegelhalder B, Bartsch H. N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori[J]. Carcinogenesis, 1997, 18(2): 383-389.
15. 　Kapil V, Haydar SM, Pearl V, et al. Physiological role for nitrate-reducing oral bacteria in blood pressure control[J]. Free Radic Biol Med, 2013, 55: 93-100.
16. 　Waddell WJ. Critique of dose response in carcinogenesis[J]. Hum Exp Toxicol, 2006, 25(7): 413-436.
17. 　Waddell WJ, Fukushima S, Williams GM. Concordance of thresholds for carcinogenicity of N-nitrosodiethylamine[J]. Arch Toxicol, 2006, 80(6): 305-309.
18. 　Abrams JA, Gonsalves L, Neugut AI. Diverging trends in the incidence of reflux-related and Helicobacter pylori-related gastric cardia cancer[J]. J Clin Gastroenterol, 2013, 47(4): 322-327.
19. 　Silva JF, Bidinotto LT, Furtado KS, et al. Maté attenuates DNA damage and carcinogenesis induced by diethylnitrosamine and thermal injury in rat esophagus[J]. Food Chem Toxicol, 2009, 47(7): 1521-1529.
20. 　Maliakal P, Sankpal UT, Basha R, et al. Relevance of drug metabolizing enzyme activity modulation by tea polyphenols in the inhibition of esophageal tumorigenesis[J]. Med Chem, 2011, 7(5): 480-487.
21. 　Yang H, Fang J, Jia X, et al. Chemopreventive effects of early-stage and late-stage supplementation of vitamin E and Selenium on esophageal carcinogenesis in rats maintained on a low vitamin E/Selenium diet[J]. Carcinogenesis, 2011, 32(3): 381-388.
22. 　Pegg AE, Perry W. Alkylation of nucleic acids and metabolism of small doses of dimethylnitrosamine in the rat[J]. Cancer Res, 1981, 41(8): 3128-3132.
23. 　Haorah J, Miller DW, Brand R, et al. Diffusion of dialkylnitrosamines into the rat esophagus as a factor in esophageal carcinogenesis[J]. Carcinogenesis, 1999, 20(5): 825-836.
24. 　Lundberg JO, Weitzberg E. Biology of nitrogen oxides in the gastrointestinal tract[J]. Gut, 2013, 62(4): 616-629.
25. 　de Castro Junior MA, Kruel CD, Meurer L, et al. Immunohistochemical expression of P53 and Ki-67 in diethylnitrosamine-induced carcinomas esophageal: experimental model[J]. Rev Col Bras Cir, 2010, 37(2): 128-134.
26. 　Hebels DG, Briedé JJ, Khampang R, et al. Radical mechanisms in nitrosamine-and nitrosamide-induced whole-genome gene expression modulations in Caco-2 cells[J]. Toxicol Sci, 2010, 116(1): 194-205.
27. 　Chen T, Stoner GD. Inducible nitric oxide synthase expression in N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis[J]. Mol Carcinog, 2004, 40(4): 232-240.
28. 　Gomez MI, Swann PF, Magee PN. The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Implication for the possible hazard of dimethylnitrosamine in human food[J]. Biochem J, 1977, 164(3): 497-500.
29. 　Yang CS, Smith T, Ishizaki, et al. Enzyme mechanisms in the metabolism of nitrosamines[J]. IARC Sci Publ, 1991(105): 265-274.
30. 　Huang Q, Stoner G, Resau J, et al. Metabolism of N-nitrosomethyl-n-amylamine by microsomes from human and rat esophagus[J]. Cancer Res, 1992, 52(13): 3547-3551.
31. 　Chowdhury G, Calcutt MW, Nagy LD, et al. Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1[J]. Biochemistry, 2012, 51(50): 9995-10007.
32. 　Loeppky RN. The mechanism of bioactivation of N-nitrosodiethanolamine[J]. Drug Metab Rev, 1999, 31(1): 175-193.
33. 　Chen T, Hwang H, Rose ME, et al. Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun[J]. Cancer Res, 2006, 66(5): 2853-2859.
34. 　Stoner GD, Chen T, Kresty LA, et al. Protection against esophageal cancer in rodents with lyophilized berries: potential mechanisms[J]. Nutr Cancer, 2006, 54(1): 33-46.
35. 　Stoner GD, Wang LS, Seguin C, et al. Multiple berry types prevent N-nitrosomethylbenzylamine-induced esophageal cancer in rats[J]. Pharm Res, 2010, 27(6): 1138-1145.

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内源性亚硝胺在食管癌一级预防中的作用及意义

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